Elastomeric functional biodegradable copolyester amides and copolyester urethanes

ABSTRACT

The present invention provides elastomeric copolyester amides, elastomeric copolyester urethanes, and methods for making the same. The polymers that are based on α-amino acids and possess suitable physical, chemical and biodegradation properties. The polymers are useful as carriers of drugs or other bioactive substances. The polymers can be linked, intermixed, or a combination thereof, to one or more drugs.

RELATED APPLICATIONS

This application is a 35 U.S.C. 371 of PCT/US01/27288, filed 30 Aug.2001 and published WO 02/18477 on 7 Mar. 2002, which claims priorityfrom U.S. patent application Ser. No. 09/651,338, filed Aug 30, 2000,now U.S. Pat. No. 6,503,538, which applications and publication areincorporated herein by reference.

BACKGROUND OF THE INVENTION

While they potentially offer many advantages due to their “organicnature,” conventional poly(α-amino acids) possess many undesirablephysical, chemical and biodegradation properties. For example, thebiological and material properties of conventional poly(α-amino acids)cannot be varied over a wide range. In addition, the synthesis of manyconventional poly(α-amino acids) is difficult and expensive.

A considerable amount of attention has therefore been focused onreplacing the amide (peptide) linkage in the conventional poly(α-aminoacids) with a variety of non-amide bonds to provide novel polymericsystems that are based on α-amino acids. One class of α-amino acidderived polymers are polyisopeptides (alternatively known aspseudo-poly(amino acids)), which belong to the XY-type heterochainpolymers. Polyisopeptides are usually formed by linking trifunctionalα-amino acids in the backbone chains. However, relatively few attemptshave been made to synthesize polyisopeptides. For example, Sekiguchi etal. obtained poly-β-(α-alkyl-L-aspartate) by the ring-openingpolymerization of β-lactams. See, Rodriguez-Galan, A. et al., Makromol.Chem., Macromol. Symp., 6, 277 (1986) and Vives, J. et al., Makromol.Chem., Rapid Commun., 10(1):13 (1989). One major limiting feature ofpolyisopeptides is that structural modifications are limited solely tochemical variations at the N-acyl residue of the polyisopeptide. Thisnarrow range of chemical modification has resulted in an undesirablynarrow range of material properties of these polymers.

Another class of α-amino acid derived polymers are amino acid basedbioanalagous polymers (AABBPs), which belong to the XX-YY heterochainpolymers. AABBPs are mainly obtained by the polycondensation of XX (onetype of monomer having two X functional groups) and YY (another type ofmonomer having two Y functional groups). AABBPs are not pure polyaminoacids or pseudo-polyamino acids because they include residues of othertypes of monomers (e.g., dicarboxylic acids and diols).

One class of AABBPs are poly(ester ureas) (PEUs), which are preparedfrom bis-α-aminoacyl diol monomers. The first attempt to usebis-α-aminoacyl(phenylalanyl) diol for preparing bioabsorbable,semi-physiological polymers similar to poly(ester urea) was by Huang etal. Huang S. J., et al., J. Appl. Polym. Sci., 23(2): 429 (1979). Onlylow-molecular-weight PEUs, having limited material properties, could beprepared by this route.

Lipatova et al. have also synthesized semi-physiological poly(esterurethane ureas) from bis-L-phenylalanyl diols, diols, and diisocyanates.Lipatova T. E., et al., Dokl. Akad. Nauk SSSR, 251(2): 368 (1980) andGladyr I. I., et al. Vysokomol. Soed., 31B(3): 196 (1989). However, noinformation on the synthesis of the starting material (e.g., α-diaminodiesters) was given.

Yoneyama et al. reported on the synthesis of high-molecular-weightsemi-physiological PEUs by the interaction of free α-diamino-diesterswith non-physiological diisocyanates. Yoneyama M., et al., Polym. Prepr.Jpn., 43(1): 177 (1994). Contrary to Huang et al. (Huang S. J., et al.,J. Appl. Polym. Sci., 23(2): 429 (1979)), high-molecular-weight PEUswere obtained in some cases. In view of this preliminary data, thereremains an ongoing need for novel polymers based on α-amino acids thatpossess a wide range of physical, chemical and biodegradationproperties.

SUMMARY OF THE INVENTION

The present invention provides polymers that are based on α-amino acids.In contrast to conventional poly(α-amino acids), the polymers of thepresent invention (e.g., elastomeric functional copolyester amides andcopolyester urethanes) possess advantageous physical, chemical andbiodegradation properties. For example, the polymers of the presentinvention possess suitable biodegradation (weight loss percent)properties under varying conditions, (see, Table III). The hydrolysis ofthe polymers can be catalyzed by hydrolases (e.g., trypsin,α-chymotrypsin, lipase, etc.). As such, the polymers can be used ascarriers for covalent immobilization (attachment) of various drugs andother bioactive substances. In addition, the enzyme catalyzedbiodegradation rates of the polymer of the present invention can bechanged by varying the polymer composition (e.g., l/p ratio) and/or thenature of the functional groups (e.g., dicarboxylic acids, diols, orα-amino acids).

The present invention provides a polymer of formula (VII):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R¹ is independently (C₂-C₂₀)alkylene;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

each R⁴ is independently (C₂-C₂₀)alkylene;

comprising one or more subunits of the formula (1):

and one or more subunits of the formula (II):

wherein

the combined number of subunits (I) and (II) is about 50 to about 150.

Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂;R² can independently be hydrogen or benzyl; each R³ can independently beiso-butyl or benzyl; and R⁴ can independently be (CH₂)₄, (CH₂)₆, (CH₂)₈,or (CH₂)₁₂.

The present invention also provides a polymer of formula (VII):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R¹ is independently (C₂-C₂₀)alkylene;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

each R⁴ is independently (C₂-C₂₀)alkylene.

Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂;each R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; p/(p+m) can be about 0.9 to about0.1; and m/(p+m) can be about 0.1 to about 0.9.

The present invention also provides a polymer of formula (VII) formedfrom an amount of one or more compounds of formula (III):

wherein

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

R⁴ is independently (C₂-C₂₀)alkylene; or a suitable salt thereof; and anamount of one or more compounds of formula (IV):

wherein

R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or a suitablesalt thereof; and

an amount of one or more compounds of formula (V):

wherein

R¹ is independently (C₂-C₂₀)alkylene; and

each R⁵ is independently (C₆-C₁₀)aryl, optionally substituted with oneor more nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy.

Specifically, R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂; R² canindependently be hydrogen or benzyl; each R³ can independently beisobutyl or benzyl; R⁴ can independently be (CH₂)₄, (CH₂)₆, (CH₂)₈, or(CH₂)₁₂; each R⁵ can independently be p-nitrophenyl; the compound offormula (III) can be the di-p-tolunesulfonic acid salt of abis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula (IV)can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester, andthe compound of formula (V) can be di-p-nitrophenyl adipate,di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate.

The present invention also provides a method for preparing a polymer offormula (VII):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R¹ is independently (C₂-C₂₀)alkylene;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

each R⁴ is independently (C₂-C₂₀)alkylene;

comprising contacting an amount of one or more compounds of formula(III):

or a suitable salt thereof; andan amount of one or more compounds of formula (IV):

or a suitable salt thereof; andan amount of one or more compounds of formula (V):

wherein

each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one ormore nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy;

under suitable conditions to provide the polymer of formula (VII).

Specifically, each R¹ can independently be (CH₂)₄, (CH₂)₈, or (CH₂)₁₂;each R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can be p-nitrophenyl; thecompound of formula (III) can be the di-p-tolunesulfonic acid salt of abis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula (IV)can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester, thecompound of formula (V) can be di-p-nitrophenyl adipate,di-p-nitrophenyl sebacinate, or di-p-nitrophenyl dodecyldicarboxylate;p/(p+m) can be about 0.9 to about 0.1; and m/(p+m) can be about 0.1 toabout 0.9. The contacting can be carried out in the presence of a base,wherein the base can be triethylamine. The contacting can also becarried out in the presence of a solvent, wherein the solvent can beN,N-dimethylacetamide. The contacting can also be carried out at atemperature of about 50° C. to about 100° C. The contacting canpreferably occur for about 10 hours to about 24 hours. The polymer offormula (VII) can also optionally be purified.

The present invention also provides a polymer of formula (XI):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R⁴ is independently (C₂-C₂)alkylene; and

each R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene;

comprising one or more subunits of the formula (VIII):

wherein

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; and

R⁴ is independently (C₂-C₂₀)alkylene;

R⁶ is independently (C₂-C₂₀)alkylene or (C₂-C₈)alkyloxy(C₂-C₂₀)alkylene;

and

one or more subunits of the formula (IX):

wherein

the total number of subunits (VIII) and (IV) is about 50 to about 150;

R² is independently hydrogen, (C₁-C₆)alkyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl.

Specifically, R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; R⁴ can independently be (CH₂)₄,(CH₂)₆, (CH₂)₈, or (CH₂)₁₂; and R⁶ can independently be (CH₂)₃ or(CH₂)₂—O—(CH₂)₂.

The present invention also provides a polymer of formula (XI):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R⁴ is independently (C₂-C₂₀)alkylene; and

each R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene.

Specifically, each R² can independently be hydrogen or benzyl; each R³can independently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁶ can independently be (CH₂)₃or (CH₂)₂—O—(CH₂)₂; p/(p+m) can be about 0.9 to about 0.1; and m/(p+m)can be about 0.1 to about 0.9.

The present invention also provides a polymer of formula (XI) formedfrom an amount of one or more compounds of formula (III):

wherein

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁C₆)alkyl; and

R⁴ is independently (C₂-C₂₀)alkylene; or a suitable salt thereof; and anamount of one or more compounds of formula (IV):

wherein

R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or a suitablesalt thereof; and

an amount of one or more compounds of formula (X):

wherein

each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one ormore nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and

R⁶ is independently (C₂-C₂₀)alkylene or (C₂-C₈)alkyloxy(C₂-C₂₀)alkylene.

Specifically, R² can independently be hydrogen or benzyl; each R³ canindependently be iso-butyl or benzyl; R⁴ can independently be (CH₂)₄,(CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can be p-nitrophenyl; R⁶ canindependently be (CH₂)₃ or (CH₂)₂—O—(CH₂)₂; the compound of formula(III) can be the di-p-tolunesulfonic acid salt of a bis-(L-α-aminoacid)α,ω-alkylene diester; the compound of formula (IV) can be thedi-p-tolunesulfonic acid salt of L-lysine benzyl ester, the compound offormula (X) can be 1,3-bis (4-nitro-phenoxycarbonyloxy) propane; or2,2′-bis-4-nitrophenoxycarbonyloxy ethylether, p/(p+m) can be about 0.9to about 0.1; and m/(p+m) can be about 0.1 to about 0.9.

The present invention also provides a method for preparing a polymer offormula (XI):

wherein

m is about 0.1 to about 0.9;

p is about 0.9 to about 0.1;

n is about 50 to about 150;

each R² is independently hydrogen or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R³ is independently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, or (C₆-C₁₀)aryl(C₁-C₆)alkyl;

each R⁴ is independently (C₂-C₂₀)alkylene;

each R⁵ is independently (C₆-C₁₀)aryl optionally substituted with one ormore nitro, cyano, halo, trifluoromethyl, or trifluoromethoxy; and

each R⁶ is independently (C₂-C₂₀)alkylene or(C₂-C₈)alkyloxy(C₂-C₂₀)alkylene;

comprising contacting an amount of one or more compounds of formula(III):

or a suitable salt thereof; andan amount of one or more compounds of formula (V):

or a suitable salt thereof; andan amount of one or more compounds of formula (X):

under suitable conditions to provide the polymer of formula (XI).

Specifically, each R² can independently be hydrogen or benzyl; each R³can independently be iso-butyl or benzyl; each R⁴ can independently be(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂; each R⁵ can be p-nitrophenyl; eachR⁶ can independently be (CH₂)₃ or (CH₂)₂—O—(CH₂)₂; the compound offormula (III) can be the di-p-tolunesulfonic acid salt of abis-(L-α-amino acid)-α,ω-alkylene diester; the compound of formula (IV)can be the di-p-tolunesulfonic acid salt of L-lysine benzyl ester, thecompound of formula (X) can be 1,3-bis (4-nitro-phenoxycarbonyloxy)propane, or 2,2′-bis-4-nitrophenoxycarbonyloxy ethylether; p/(p+m) canbe about 0.9 to about 0.1; and m/(p+m) can be about 0.1 to about 0.9.The contacting can be carried out in the presence of a base, wherein thebase can be triethylamine. The contacting can be carried out in thepresence of a solvent, wherein the solvent can be N,N-dimethylacetamide.The contacting can be carried out at a temperature of about 50° C. toabout 100° C. The contacting can occur for about 10 hours to about 24hours. In addition, the polymer of formula (XI) can optionally bepurified.

The biodegradation of the copolyester amides and copolyester urethanesof the present invention allows the delivery of essential α-amino acidsto targeted sites (e.g., to facilitate wound repair of injured tissues).In addition, the polymers of the present invention can be used for theattachment free iminoxyl radicals for suppressing inconsolable cellproliferation, and heparin or hirudin for increasing hemocompatibility.These modified polymers can be used to coat stents to suppressrestenosis. In addition, the polymers of the present invention can beused as polyacids for the application in gynecology as impregnatedcontraceptive agents, e.g., for the controlled release of ferrousgluconate and the like. Furthermore, the polymers of the presentinvention can be used as polyacids for the attachment of unsaturatedcompounds, e.g., allyl amine or allyl alcohol, to obtain photo-curableand cross-linkable biodegradable polymers. The present polymers can becross-linked with other polymers containing double bonds to createhybrid materials.

The biological and material properties of the polymers of the presentinvention can be varied over a wide range because the polymers can beformed from starting materials having varying functional groups (e.g.,dicarboxylic acids, diols, and α-amino acids). See, e.g., Examples 1-22.In contrast to conventional poly(α-amino acids), the elastomericfunctional copolyester amides and copolyester urethanes of the presentinvention can be obtained in high yields. See, Table III. For example,the compounds of the present invention can be prepared in yields up toabout 97%. In addition, the reaction conditions employed to prepare thepolymers of the present invention are relatively simple and the reagentsare relatively inexpensive.

The present invention also provides a polymer of formula (VII) that islinked to one or more drugs. The present invention also provides apolymer of formula (XI) that is linked to one or more drugs. A residueof the polymer can be linked directly to a residue of the drug. Theresidue of the polymer can be linked directly to the residue of the drugthrough an amide, ester, ether, amino, ketone, thioether, sulfinyl,sulfonyl, disulfide, or a direct linkage. The residue of the polymer canbe linked directly to the residue of the drug through one of thefollowing linkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—C(═O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R isindependently H or (C₁-C₆)alkyl.

A residue of the polymer can be linked to a residue of the drug, througha linker. The linker can separate the residue of the polymer and theresidue of the drug by about 5 angstroms to about 200 angstroms,inclusive, in length. The residue of the polymer can be linked to thelinker and the linker can be linked to the residue of the drug,independently, through an amide, ester, ether, amino, ketone, thioether,sulfinyl, sulfonyl, disulfide, or a direct linkage. The residue of thepolymer can be linked to the linker and the linker can be linked to theresidue of the drug, independently, through one of the followinglinkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —C(═O)—,—S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R isindependently H or (C₁-C₆)alkyl. The linker can be a divalent radical ofthe formula W-A-Q wherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl,(C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl, wherein W and Q areeach independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, —C(═O)—, or a direct bond; whereineach R is independently H or (C₁-C₆)alkyl. The linker can be a1,ω-divalent radical formed from a peptide or an amino acid. The peptidecan comprise 2 to about 25 amino acids. The peptide can bepoly-L-lysine, poly-L-glutamic acid, poly-L-aspartic acid,poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine,poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine,poly-L-arginine, or poly-L-lysine-L-tyrosine.

The one or more drugs can each independently be: a polynucleotide,polypeptide, oligonucleotide, gene therapy agent, nucleotide analog,nucleoside analog, polynucleic acid decoy, therapeutic antibody,abciximab, anti-inflammatory agent, blood modifier, anti-platelet agent,anti-coagulation agent, immune suppressive agent, anti-neoplastic agent,anti-cancer agent, anti-cell proliferation agent, or nitric oxidereleasing agent.

The present invention also provides a formulation comprising a polymerof formula (VII) and one or more drugs. The present invention alsoprovides a formulation comprising a polymer of formula (XI) and one ormore drugs. The one or more drugs can each independently be: apolynucleotide, polypeptide, oligonucleotide, gene therapy agent,nucleotide analog, nucleoside analog, polynucleic acid decoy,therapeutic antibody, abciximab, anti-inflammatory agent, bloodmodifier, anti-platelet agent, anti-coagulation agent, immunesuppressive agent, anti-neoplastic agent, anti-cancer agent, anti-cellproliferation agent, or nitric oxide releasing agent.

The present invention also provides a method of using a polymer of thepresent invention for use as a medical device, a pharmaceutical, acarrier for covalent immobilization of a drug, or a bioactive substance.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the biodegradation (weight loss in mg/cm²) of 4-aminoTEMPO (“TAM”) attached to a representative compound, co-PEA, accordingto one embodiment.

FIG. 2 illustrates the kinetics of nitroxyl radical release from TAMattached to a representative compound, co-PEA, according to anembodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described: halo canbe chloro, fluoro, bromo, or iodo. Alkyl, alkenyl, alkynyl, etc. denoteboth straight and branched groups; but reference to an individualradical such as “propyl” embraces only the straight chain radical, abranched chain isomer such as “isopropyl” being specifically referredto.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase).

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain preferably having from 1 to 40 carbon atoms,more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6carbon atoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, -butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl,and the like. As used herein, “alkyl” includes “substituted alkyl,”which refers to an alkyl group as defined above, having from 1 to 8substituents, preferably 1 to 5 substituents, and more preferably 1 to 3substituents, selected from the group consisting of alkoxy, cycloalkyl,acyl, amino, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy,thiol, aryl, heteroaryl, heterocyclic, and nitro.

The term “alkaryl” refers to the groups -alkylene-aryl and -substitutedalkylene-aryl where alkylene, substituted alkylene and aryl are definedherein. Such alkaryl groups are exemplified by benzyl, phenethyl and thelike.

The term “alkoxy” refers to the groups allyl-O—, alkenyl-O—,cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl,cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferredalkoxy groups are alkyl-O— and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. As used herein,“alkoxy” includes “substituted alkoxy,” which refers to the groupssubstituted alkyl-O—, substituted alkenyl-O—, substituted cycloatkyl-O—,substituted cycloalkenyl-O—, and substituted alkynyl-O— wheresubstituted alkyl, substituted alkenyl, substituted cycloalkyl,substituted cycloalkenyl and substituted alkynyl are as defined herein.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group preferably having from 2 to 40 carbonatoms, more preferably 2 to 10 carbon atoms and even more preferably 2to 6 carbon atoms and having at least 1 and preferably from 1-6 sites ofvinyl unsaturation. Preferred alkenyl groups include ethenyl (—CH═CH₂),in-propenyl (—CH₂CH═CH₂), iso-propenyl (—C(CH₃)═CH₂), and the like. Asused herein, “alkenyl” includes “substituted alkenyl,” which refers toan alkenyl group as defined above having from 1 to 5 substituents, andpreferably 1 to 3 substituents, selected from the group consisting ofalkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino,substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano,halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbonpreferably having from 2 to 40 carbon atoms, more preferably 2 to 20carbon atoms and even more preferably 2 to 6 carbon atoms and having atleast 1 and preferably from 1-6 sites of acetylene (triple bond)unsaturation. Preferred alkynyl groups include ethynyl (—C≡CH),propargyl (—CH₂C≡CH) and the like. As used herein, “alkynyl” includes“substituted alkynyl,” which refers to an alkynyl group as defined abovehaving from 1 to 5 substituents, and preferably 1 to 3 substituents,selected from the group consisting of alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “acyl” refers to the groups HC(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 20 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings, wherein at least one ring is aromatic(e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferredaryls include phenyl, naphthyl and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with from 1 to 5substituents, preferably 1 to 3 substituents, selected from the groupconsisting of hydroxy, thiol, acyl, alkyl alkoxy, alkenyl, alkynyl,cycloalkyl aryl, azido, carboxy, cyano, halo, nitro, heteroaryl,heterocyclic, sulfonamide. Preferred aryl substituents include alkyl,alkoxy, halo, cyano, nitro, and trihalomethyl.

The term “amino” refers to the group —NH₂.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.As used herein, “cycloalkyl” includes “substituted cycloalkyl,” whichrefers to cycloalkyl groups having from 1 to 5 substituents, andpreferably 1 to 3 substituents, selected from the group consisting ofalkoxy, cycloalkyl, acyl, amino, azido, cyano, halogen, hydroxyl, keto,carboxy, thiol, aryl, heteroaryl, heterocyclic, and nitro.

The term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to allyl as defined herein substituted by 1-4 halogroups as defined herein, which may be the same or different.Representative haloalkyl groups include, by way of example,trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl,2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.

The term “heteroaryl” refers to an aromatic group of from 1 to 15 carbonatoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfurwithin at least one ring (if there is more than one ring).

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1 to 3 substituents, selected from thegroup consisting of hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl,alkynyl, cycloalkyl, alkaryl, aryl, azido, carboxy, cyano, halo, nitro,heteroaryl, and heterocyclic. Preferred aryl substituents include alkyl,alkoxy, halo, cyano, nitro, and trihalomethyl. Such heteroaryl groupscan have a single ring (e.g., pyridyl or furyl) or multiple condensedrings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls includepyridyl, pyrrolyl and furyl.

The term “heterocycle” or “heterocyclic” refers to a monoradicalsaturated or unsaturated group having a single ring or multiplecondensed rings, from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and preferably 1 to 3 substituents, selected from the groupconsisting of alkoxy, cycloalkyl, acyl, amino, azido, cyano, halogen,hydroxyl, keto, carboxy, thiol, aryl, and heterocyclic. Suchheterocyclic groups can have a single ring or multiple condensed rings.Preferred heterocyclics include morpholino, piperidinyl, and the like.

Examples of nitrogen heterocycles and heteroaryls include, but are notlimited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

The term “saccharide group” refers to an oxidized, reduced orsubstituted saccharide monoradical covalently attached to theglycopeptide or other compound via any atom of the saccharide moiety,preferably via the aglycone carbon atom. The term includesamino-containing saccharide groups. Representative saccharides include,by way of illustration, hexoses such as D-glucose, D-mannose, D-xylose,D-galactose, vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine,4-epi-vancosamine, acosamine, actinosamine, daunosamine,3-epi-daunosamine, ristosamine, D-glucamine, N-methyl-D-glucamine,D-glucuronic acid, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine,sialyic acid, iduronic acid, L-fucose, and the like; pentoses such asD-ribose or D-arabinose; ketoses such as D-ribulose or D-fructose;disaccharides such as 2-O-(α-L-vancosaminyl)-β-D-glucopyranose,2-O-(3-desmethyl-α-L-vancosaminyl)-β-D-glucopyranose, sucrose, lactose,or maltose; derivatives such as acetals, amines, acylated, sulfated andphosphorylated sugars; oligosaccharides having from 2 to 10 saccharideunits. For the purposes of this definition, these saccharides arereferenced using conventional three letter nomenclature and thesaccharides can be either in their open or preferably in their pyranoseform. The “saccharide group” includes “amino-containing saccharidegroup” or “amino saccharide,” which refers to a saccharide group havingan amino substituent. Representative amino-containing saccharidesinclude L-vancosamine, 3-desmethyl-vancosamine, 3-epi-vancosamine,4-epi-vancosamine, acosamine, actinosamine, daunosamine,3-epi-daunosamine, ristosamine, N-methyl-D-glucamine and the like.

The term “stereoisomer” as it relates to a given compound is wellunderstood in the art, and refers another compound having the samemolecular formula, wherein the atoms making up the other compound differin the way they are oriented in space, but wherein the atoms in theother compound are like the atoms in the given compound with respect towhich atoms are joined to which other atoms (e.g. an enantiomer, adiastereomer, or a geometric isomer). See for example, Morrison andBoyde Organic Chemistry, 1983, 4th ed., Allyn and Bacon, Inc., Boston,Mass., page 123.

The term “thiol” refers to the group —SH.

As to any of the above groups which contain one or more substituents, itis understood, of course, that such groups do not contain anysubstitution or substitution patterns which are sterically impracticaland/or synthetically non-feasible. In addition, the compounds of thisinvention include all stereochemical isomers arising from thesubstitution of these compounds.

“Cyclodextrin” refers to cyclic molecules containing six or moreα-D-glucopyranose units linked at the 1,4 positions by a linkages as inamylose. β-Cyclodextrin or cycloheptaamylose contains sevenα-D-glucopyranose units. As used herein, the term “cyclodextin” alsoincludes cyclodextrin derivatives such as hydroxypropyl and sulfobutylether cyclodextrins, and others. Such derivatives are described forexample, in U.S. Pat. Nos. 4,727,064 and 5,376,645. Additionally,hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin arecommercially available. One preferred cyclodextrin is hydroxypropylβ-cyclodextrin having a degree of substitution of from about 4.1-5.1 asmeasured by FUR. Such a cyclodextrin is available from Cerestar(Hammond, Ind., USA) under the name Cavitron™ 82003.

As used herein, an “amino acid” is a natural amino acid residue (e.g.Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys,Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as well asunnatural amino acid (e.g. phosphoserine; phosphothreonine;phosphotyrosine; hydroxyproline; gamma-carboxyglutamate; hippuric acid;octahydroindole-2-carboxylic acid; statine;1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid; penicillamine;ornithine; citruline; α-methyl-alanine; para-benzoylphenylalanine;phenylglycine; propargylglycine; sarcosine; and tert-butylglycine)residue having one or more open valences. The term also comprisesnatural and unnatural amino acids bearing amino protecting groups (e.g.acetyl, acyl, trifluoroacetyl, or benzyloxycarbonyl), as well as naturaland unnatural amino acids protected at carboxy with protecting groups(e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide). Othersuitable amino and carboxy protecting groups are known to those skilledin the art (See for example, T. W. Greene, Protecting Groups In OrganicSynthesis; Wiley: New York, 1981; D. Voet, Biochemistry, Wiley: NewYork, 1990; L. Stryer, Biochemistry, (3rd Ed.), W. H. Freeman and Co.:New York, 1975; J. March, Advanced Organic Chemistry. Reactions,Mechanisms and Structure, (2nd Ed.), McGraw Hill: New York, 1977; F.Carey and R. Sundberg, Advanced Organic Chemistry. Part B: Reactions andSynthesis, (2nd Ed.), Plenum: New York, 1977; and references citedtherein). According to the invention, the amino or carboxy protectinggroup can also comprise a non-metallic radionuclide (e.g., Fluorine-18,Iodine-123, or Iodine-124).

The term “amino acid” includes alpha amino acids and beta amino acids.The alpha amino acids include monocarboxylic monoamino acids,dicarboxylic monoamino acids, polyamino acids and heterocyclic aminoacids. Examples of monocarboxylic monoamino acids include glycine,alpha-phenylglycine, alpha-alanine, serine, valine, norvaline,beta-mercaptovaline, threonine, cysteine, leucine, isoleucine,norleucine, N-methylleucine, beta-hydroxy leucine, methionine,phenylalanine, N-methylphenylalanine, pipecolic acid, sarcosine,selenocysteine, tyrosine, 3,5-diiodotyrosine, triiodothyronine, andthyroxine. Examples of monoamino dicarboxylic acids and amides includeaspartic acid, beta-methyl aspartic acid, glutamic acid, asparagine,alpha-aminoadipic acid, 4-keto-pipecolic acid, lanthionine, andglutamine. Examples of polyamino acids include ornithine, lysine,6-N-methyllysine, 5-hydroxylysine, desmosine, arginine and cystine.Examples of heterocyclic amino acids include proline, 4-hydroxyprolineand histidine, and tryptophan. Examples of other alpha amino acids aregamma-carboxyglutamate and citrulline. The beta amino acids include, forexample, beta-alanine.

As used herein, a “peptide” is a sequence of 2 to 25 amino acids (e.g.as defined hereinabove) or peptidic residues having one or more openvalences. The sequence may be linear or cyclic. For example, a cyclicpeptide can be prepared or may result from the formation of disulfidebridges between two cysteine residues in a sequence. A peptide can belinked through the carboxy terminus, the amino terminus, or through anyother convenient point of attachment, such as, for example, through thesulfur of a cysteine. Peptide derivatives can be prepared as disclosedin U.S. Pat. Nos. 4,612,302; 4,853,371; and 4,684,620. Peptide sequencesspecifically recited herein are written with the amino terminus on theleft and the carboxy terminus on the right.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

A specific value for R¹ is (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.

A specific value for R² is hydrogen, benzyl, or phenethyl. Anotherspecific value for R² is benzyl.

A specific value for R³ is iso-butyl or benzyl.

A specific value for R⁴ is (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.

A specific value for R⁵ is p-nitrophenyl.

A specific value for R⁶ is (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.

A specific value for m is about 0.25 to about 0.75.

A specific value for p is about 0.75 to about 0.25.

A specific value for n is about 75 to about 125.

A specific value for p/(p+m) is about 0.75 to about 0.25.

A specific value for m/(p+m) is about 0.25 to about 0.75.

A specific value for (p+m) is about 0.9 to about 1.1. Another specificvalue for (p+m) is about 0.75 to about 1.25.

A specific group of compounds of formula (III) are thedi-p-tolunesulfonic acid salts of a bis-(L-α-amino acid)α,ω-alkylenediester:

wherein

-   -   each R³ is independently iso-butyl or benzyl; and    -   R⁴ is (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.

A specific group of compounds of formula (IV) are thedi-p-tolunesulfonic acid salts of L-lysine arylalkyl esters:

wherein

R² is benzyl or phenethyl. More specifically, R² can be benzyl.

A specific group of compounds of formula (V) are compounds of theformula:

wherein

R¹ is (CH₂)₄ (CH₂)₈, or (CH₂)₁₂; and

R⁵ is p-nitrophenyl.

For example, a specific group of compounds of formula (V) aredi-p-nitrophenyl adipate, di-p-nitrophenyl sebacinate, anddi-p-nitrophenyl dodecyldicarboxylate

A specific group of compounds of formula (X) are compounds of theformula:

wherein

R⁵ is p-nitrophenyl; and

R⁶ is (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.

For example, a specific group of compounds of formula (X) are 1,3-bis(4-nitro-phenoxycarbonyloxy) propane and2,2′-bis-4-(nitrophenoxycarbonyloxy)ethylether.

In cases where compounds (e.g., starting materials) are sufficientlybasic or acidic to form stable nontoxic acid or base salts, thecompounds can exist as the acceptable salt. Examples of acceptable saltsare organic acid addition salts formed with acids which form anacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tararate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso exist, including hydrochloride, sulfate, nitrate, bicarbonate, andcarbonate salts.

Acceptable salts may be obtained by using standard procedures that arewell known in the art, for example by reacting a sufficiently basiccompound such as an amine with a suitable acid affording an acceptableanion. Alkali metal (for example, sodium, potassium or lithium) oralkaline earth metal (for example calcium) salts of carboxylic acids canalso be made.

Processes for preparing polymers of the present invention (e.g.,polymers of formula (VII) and polymers of formula (XI)) are provided asfurther embodiments of the invention and are illustrated by theprocedures herein below in which the meanings of the generic radicalsare as given above unless otherwise qualified.

A polymer of formula (VII) can include one or more subunits of formula(I) and one or more subunits of formula (II); As such, a polymer offormula (VII) can be prepared from a compound of formula (III), from acompound of formula (IV), and from a compound of formula (V).Specifically, a polymer of formula (VII) can be prepared by contacting acompound of formula (III), a compound of formula (IV), and a compound offormula (V) under suitable conditions to provide a polymer of formula(VII).

The compounds of formula (III), (IV), and (V) can be contacted in thepresence of a solvent. Any suitable solvent can be employed. When thecompounds of formula (III), (IV), and (V) are contacted in the presenceof a solvent, the compounds of formula (III), (IV), and (V) arepreferably soluble in the solvent. One exemplary suitable solvent isN,N-dimethylacetamide.

The compounds of formula (III), (IV), and (V) can be contacted in thepresence of a base. Any suitable base can be employed. When thecompounds of formula (III), (IV), and (V) are contacted in the presenceof a base, the base will preferably adjust the initial pH of thereaction mixture (i.e., the solution including the compounds of formula(III), (IV), and (V)) above about 7. The base is useful to yield thefree amines of the compound of formula (III) and the compound of formula(IV). One exemplary suitable base is triethylamine.

The compounds of formula (III), (IV), and (V) can be contacted for aperiod of time sufficient to provide the polymer of formula (VII). Forexample, the period of time can be from about 1 hour to about 48 hours,inclusive. Preferably, the period of time can be from about 5 hours toabout 30 hours, inclusive. More preferably, the period of time can befrom about 10 hours to about 24 hours, inclusive.

The compounds of formula (III), (IV), and (V) can be contacted at atemperature sufficient to provide the polymer of formula (VII). Forexample, the temperature can be from the freezing point of the liquidreaction mixture (e.g., the solvent, base, and the compounds of formula(III), (IV), and (V)) up to about the reflux temperature of the reactionmixture. Preferably, the temperature can be from about 25° C. to about150° C. More preferably, the temperature can be from about 50° C. toabout 100° C.

A polymer of formula (XI) can include one or more subunits of formula(VIII) and one or more subunits of formula (IX). As such, a polymer offormula (XI) can be prepared from a compound of formula (III), from acompound of formula (IV), and from a compound of formula (X).Specifically, a polymer of formula (XI) can be prepared by contacting acompound of formula (III), a compound of formula (IV), and a compound offormula (X) under suitable conditions to provide a polymer of formula(XI).

The compounds of formula (III), (IV), and (X) can be contacted in thepresence of a solvent. Any suitable solvent can be employed. When thecompounds of formula (III), (IV), and (X) are contacted in the presenceof a solvent, the compounds of formula (III), (IV), and (X) arepreferably soluble in the solvent. One exemplary suitable solvent isN,N-dimethylacetamide.

The compounds of formula (III), (IV), and (X) can be contacted in thepresence of a base. Any suitable base can be employed. When thecompounds of formula (III), (IV), and (X) are contacted in the presenceof a base, the base will preferably adjust the initial pH of thereaction mixture (i.e., the solution including the compounds of formula(III), (IV), and (X)) above about 7. The base is useful to yield thefree amines of the compound of formula (III) and the compound of formula(IV). One exemplary suitable base is triethylamine.

The compounds of formula (III) (IV), and (X) can be contacted for aperiod of time sufficient to provide the polymer of formula (VII). Forexample, the period of time can be from about 1 hour to about 48 hours,inclusive. Preferably, the period of time can be from about 5 hours toabout 30 hours, inclusive. More preferably, the period of time can befrom about 10 hours to about 24 hours, inclusive.

The compounds of formula (III), (IV), and (X) can be contacted at atemperature sufficient to provide the polymer of formula (VII). Forexample, the temperature can be from about the freezing point of theliquid reaction mixture (e.g., the solvent, base, and the compounds offormula (III) (IV), and (X)) up to about the reflux temperature of thereaction mixture. Preferably, the temperature can be from about 25° C.to about 150° C. More preferably, the temperature can be from about 50°C. to about

Polymer and Drug

A polymer of the present invention can include one or more drugs. In oneembodiment, a polymer of the present invention can be physicallyintermixed with one or more drugs. In another embodiment, a polymer ofthe present invention can be linked to one or more drugs, eitherdirectly or through a linker. In another embodiment, a polymer of thepresent invention can be linked to one or more drugs, either directly orthrough a linker, and the resulting polymer can be physically intermixedwith one or more drugs.

As used herein, a “polymer of the present invention” includes a compoundof formula (VII), a compound of formula (XI), or a combination thereof.

Polymer/Drug Linkage

The present invention provides a polymer of the present invention (e.g.,a compound of formula (VII) or a compound of formula (XI)) directlylinked to one or more drugs. In such an embodiment, the residues of thepolymer can be linked to the residues of the one or more drugs. Forexample, one residue of the polymer can be directly linked to oneresidue of the drug. The polymer and the drug can each have one openvalence. Alternatively, more than one drug can be directly linked to thepolymer. In such an embodiment, the residue of each drug can be linkedto a corresponding residue of the polymer. As such, the number ofresidues of the one or more drugs can correspond to the number of openvalences on the residue of the polymer.

As used herein, a “residue of a polymer of the present invention” refersto a radical of a polymer of the present invention having one or moreopen valences. Any synthetically feasible atom, atoms, or functionalgroup of the polymer (e.g., on the polymer backbone or pendant group) ofthe present invention can be removed to provide the open valence,provided bioactivity is substantially retained when the radical isattached to a residue of a drug. Additionally, any syntheticallyfeasible functional group (e.g., carboxyl) can be created on the polymer(e.g., on the polymer backbone or pendant group) to provide the openvalence, provided bioactivity is substantially retained when the radicalis attached to a residue of a drug. Based on the linkage that isdesired, one skilled in the art can select suitably functionalizedstarting materials that can be derived from the polymer of the presentinvention using procedures that are known in the art.

As used herein, a “residue of a compound of formula (VII)” refers to aradical of a compound of formula (VII) having one or more open valences.Any synthetically feasible atom, atoms, or functional group of thecompound of formula (VII) (e.g., on the polymer backbone or pendantgroup) can be removed to provide the open valence, provided bioactivityis substantially retained when the radical is attached to a residue of adrug. Additionally, any synthetically feasible functional group (e.g.,carboxyl) can be created on the compound of formula (VII) (e.g., on thepolymer backbone or pendant group) to provide the open valence, providedbioactivity is substantially retained when the radical is attached to aresidue of a drug. Based on the linkage that is desired, one skilled inthe art can select suitably functionalized staring materials that can bederived from the compound of formula (VII) using procedures that areknown in the art.

As used herein, a “residue of a compound of formula (XI)” refers to aradical of a compound of formula (XI) having one or more open valences.Any synthetically feasible atom, atoms, or functional group of thecompound of formula (XI) (e.g., on the polymer backbone or pendantgroup) can be removed to provide the open valence, provided bioactivityis substantially retained when the radical is attached to a residue of adrug. Additionally, any synthetically feasible functional group (e.g.,carboxyl) can be created on the compound of formula (XI) (e.g., on thepolymer backbone or pendant group) to provide the open valence, providedbioactivity is substantially retained when the radical is attached to aresidue of a drug. Based on the linkage that is desired, one skilled inthe art can select suitably functionalized starting materials that canbe derived from the compound of formula (XI) using procedures that areknown in the art.

The residue of a drug can be linked to the residue of a compound offormula (VII) or (XI) through an amide (e.g., —N(R)C(═O)— or—C(═O)N(R)—), ester (e.g., —OC(═O)— or —C(═O)O—), ether (e.g., —O—),amino (e.g., —N(R)—), ketone (e.g., —C(═O)—), thioether (e.g., —S—),sulfinyl (e.g., —S(O)—), sulfonyl (e.g., —S(O)₂—), disulfide (e.g.,—S—S—), or a direct (e.g., C—C bond) linkage, wherein each R isindependently H or (C₁-C₆)alkyl. Such a linkage can be formed fromsuitably functionalized starting materials using synthetic proceduresthat are known in the art. Based on the linkage that is desired, oneskilled in the art can select suitably functional starting materialsthat can be derived from a residue of a compound of formula (VII) or(XI) and from a given residue of a drug using procedures that are knownin the art. The residue of the drug can be directly linked to anysynthetically feasible position on the residue of a compound of formula(VII) or (XI). Additionally, the invention also provides compoundshaving more than one residue of a drug or drugs directly linked to acompound of formula (VII) or (XI).

One or more drugs can be linked directly to the polymer. Specifically,the residue of each of the drugs can each be directly linked to theresidue of the polymer. Any suitable number of drugs (i.e., residuesthereof) can be directly linked to the polymer (i.e., residue thereof).The number of drugs that can be directly linked to the polymer cantypically depend upon the molecular weight of the polymer. For example,for a compound of formula (VII), wherein n is about 50 to about 150, upto about 450 drugs (i.e., residues thereof) can be directly linked tothe polymer (i.e., residue thereof), up to about 300 drugs (i.e.,residues thereof) can be directly linked to the polymer (i.e., residuethereof), or up to about 150 drugs (i.e., residues thereof) can bedirectly linked to the polymer (i.e., residue thereof). Likewise, for acompound of formula (XI), wherein n is about 50 to about 150, up toabout 450 drugs (i.e., residues thereof) can be directly linked to thepolymer (i.e., residue thereof), up to about 300 drugs (i.e., residuesthereof) can be directly linked to the polymer (i.e., residue thereof),or up to about 150 drugs (i.e., residues thereof) can be directly linkedto the polymer (i.e., residue thereof).

The residue of a polymer of the present invention, the residue of acompound of formula (VII), and/or the residue of a compound of formula(XI) can be formed employing any suitable reagents and reactionconditions. Suitable reagents and reaction conditions are disclosed,e.g., in Advanced Organic Chemistry Part B: Reactions and Synthesis,Second Edition, Carey and Sundberg (1983); Advanced Organic Chemistry,Reactions, Mechanisms, and Structure, Second Edition, March (1977); andComprehensive Organic Transformations, Second Edition, Larock (1999).

In one embodiment of the present invention, a polymer (i.e., residuethereof) of the present invention can be linked to the drug (i.e.,residue thereof) via the carboxyl group (e.g., COOR²) of the polymer.Specifically, a compound of formula (VII), wherein R² is independentlyhydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; a compound of formula (XI),wherein R² is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or acombination thereof, can react with an amino functional group of thedrug or a hydroxyl functional group of the drug, to provide aPolymer/Drug having an amide linkage or a Polymer/Drug having acarboxylic ester linkage, respectively. In another embodiment, thecarboxyl group of the polymer can be transformed into an acyl halide oran acyl anhydride.

Drug

As used herein, a “drug” refers to a therapeutic agent or a diagnosticagent and includes any substance, other than food, used in theprevention, diagnosis, alleviation, treatment, or cure of a disease.Stedman's Medical Dictionary, 25^(th) Edition, Illustrated (1990) p.486. The substance can be taken by mouth; injected into a muscle, theskin, a blood vessel, or a cavity of the body; or topically applied.Mosby's Medical, Nursing & Allied Health Dictionary, Fifth Edition,(1998) p. 516. The drug can include any substance disclosed in at leastone of: The Merck Index, 12^(th) Edition (1996); Concise Dictionary ofBiomedicine and Molecular Biology, Pei-Show Juo, (1996); U.S.Pharmacopeia Dictionary, 2000 Edition; and Physician's Desk Reference,2001 Edition.

Specifically, the drug can include, but is not limited to, one or more:polynucleotides, polypeptides, oligonucleotides, gene therapy agents,nucleotide analogs, nucleoside analogs, polynucleic acid decoys,therapeutic antibodies, abciximab, anti-inflammatory agents, bloodmodifiers, anti-platelet agents, anti-coagulation agents, immunesuppressive agents, anti-neoplastic agents, anti-cancer agents,anti-cell proliferation agents, and nitric oxide releasing agents.

The polynucleotide can include deoxyribonucleic acid (DNA), ribonucleicacid (RNA), double stranded DNA, double stranded RNA, duplex DNA/RNA,antisense polynucleotides, functional RNA or a combination thereof. Inone embodiment, the polynucleotide can be RNA. In another embodiment,the polynucleotide can be DNA In another embodiment, the polynucleotidecan be an antisense polynucleotide. In another embodiment, thepolynucleotide can be a sense polynucleotide. In another embodiment, thepolynucleotide can include at least one nucleotide analog. In anotherembodiment, the polynucleotide can include a phosphodiester linked 3′-5′and 5′-3′ polynucleotide backbone. Alternatively, the polynucleotide caninclude non-phosphodiester linkages, such as phosphotioate type,phosphoramidate and peptide-nucleotide backbones. In another embodiment,moieties can be linked to the backbone sugars of the polynucleotide.Methods of creating such linkages are well known to those of skill inthe art.

The polynucleotide can be a single-stranded polynucleotide or adouble-stranded polynucleotide. The polynucleotide can have any suitablelength. Specifically, the polynucleotide can be about 2 to about 5,000nucleotides in length, inclusive; about 2 to about 1000 nucleotides inlength, inclusive; about 2 to about 100 nucleotides in length,inclusive; or about 2 to about 10 nucleotides in length, inclusive.

An antisense polynucleotide is typically a polynucleotide that iscomplimentary to an mRNA, which encodes a target protein. For example,the mRNA can encode a cancer promoting protein i.e., the product of anoncogene. The antisense polynucleotide is complimentary to the singlestranded mRNA and will form a duplex and thereby inhibit expression ofthe target gene, i.e., will inhibit expression of the oncogene. Theantisense polynucleotides of the invention can form a duplex with themRNA encoding a target protein and will disallow expression of thetarget protein.

A “functional RNA” refers to a ribozyme or other RNA that is nottranslated.

A “polynucleic acid decoy” is a polynucleic acid which inhibits theactivity of a cellular factor upon binding of the cellular factor to thepolynucleic acid decoy. The polynucleic acid decoy contains the bindingsite for the cellular factor. Examples of cellular factors include, butare not limited to, transcription factors, polymerases and ribosomes. Anexample of a polynucleic acid decoy for use as a transcription factordecoy will be a double stranded polynucleic acid containing the bindingsite for the transcription factor. Alternatively, the polynucleic aciddecoy for a transcription factor can be a single stranded nucleic acidthat hybridizes to itself to form a snap-back duplex containing thebinding site for the target transcription factor. An example of atranscription factor decoy is the E2F decoy. E2F plays role intranscription of genes that are involved with cell-cycle regulation andthat cause cells to proliferate. Controlling E2F allows regulation ofcellular proliferation. For example, after injury (e.g., angioplasty,surgery, stenting) smooth muscle cells proliferate in response to theinjury. Proliferation may cause restenosis of the treated area (closureof an artery through cellular proliferation). Therefore, modulation ofE2F activity allows control of cell proliferation and can be used todecrease proliferation and avoid closure of an artery. Examples of othersuch polynucleic acid decoys and target proteins include, but are notlimited to, promoter sequences for inhibiting polymerases and ribosomebinding sequences for inhibiting ribosomes. It is understood that theinvention includes polynucleic acid decoys constructed to inhibit anytarget cellular factor.

A “gene therapy agent” refers to an agent that causes expression of agene product in a target cell through introduction of a gene into thetarget cell followed by expression. An example of such a gene therapyagent would be a genetic construct that causes expression of a protein,such as insulin, when introduced into a cell. Alternatively, a genetherapy agent can decrease expression of a gene in a target cell. Anexample of such a gene therapy agent would be the introduction of apolynucleic acid segment into a cell that would integrate into a targetgene and disrupt expression of the gene. Examples of such agents includeviruses and polynucleotides that are able to disrupt a gene throughhomologous recombination. Methods of introducing and disrupting geneswith cells are well known to those of skill in the art.

An oligonucleotide of the invention can have any suitable length.Specifically, the oligonucleotide can be about 2 to about 100nucleotides in length, inclusive; up to about 20 nucleotides in length,inclusive; or about 15 to about 30 nucleotides in length, inclusive. Theoligonucleotide can be single-stranded or double-stranded. In oneembodiment, the oligonucleotide can be single stranded. Theoligonucleotide can be DNA or RNA. In one embodiment, theoligonucleotide can be DNA In one embodiment, the oligonucleotide can besynthesized according to commonly known chemical methods. In anotherembodiment, the oligonucleotide can be obtained from a commercialsupplier. The oligonucleotide can include, but is not limited to, atleast one nucleotide analog, such as bromo derivatives, azidoderivatives, fluorescent derivatives or a combination thereof.Nucleotide analogs are well known to those of skill in the art. Theoligonucleotide can include a chain terminator. The oligonucleotide canalso be used, e.g., as a cross linking reagent or a fluorescent tag.Many common linkages can be employed to couple an oligonucleotide of theinvention to another moiety, e.g., phosphate, hydroxyl, etc.Additionally, a moiety may be linked to the oligonucleotide through anucleotide analog incorporated into the oligonucleotide. In anotherembodiment, the oligonucleotide can include a phosphodiester linked3′-5′ and 5′-3′ oligonucleotide backbone. Alternatively, theoligonucleotide can include non-phosphodiester linkages, such asphosphotioate type, phosphoramidate and peptide-nucleotide backbones. Inanother embodiment, moieties can be linked to the backbone sugars of theoligonucleotide. Methods of creating such linkages are well known tothose of skill in the art.

Nucleotide and nucleoside analogues are well known on the art. Examplesof such nucleoside analogs include, but are not limited to, Cytovene®(Roche Laboratories), Epivir® (Glaxo Wellcome), Gemzar® (Lilly), Hivid®(Roche Laboratories), Rebetron®) (Schering), Videx® (Bristol-MyersSquibb), Zerit® (Bristol-Myers Squibb), and Zovirax® (Glaxo Wellcome).See, Physician's Desk Reference, 2001 Edition.

Polypeptides of the invention can have any suitable length.Specifically, the polypeptides can be about 2 to about 5,000 amino acidsin length, inclusive; about 2 to about 2,000 amino acids in length,inclusive; about 2 to about 1,000 amino acids in length, inclusive; orabout 2 to about 100 amino acids in length, inclusive.

The polypeptides of the invention can also include “Peptide mimetics”.Peptide analogs are commonly used in the pharmaceutical industry asnon-peptide drugs with properties analogous to those of the templatepeptide. These types of non-peptide compound are termed “peptidemimetics” or “peptidomimetics”. Fauchere, J. (1986) Adv. Drug Res.,15:29; Veber and Freidinger (1985) TINS p. 392; and Evans et al. (1987)J. Med. Chem., 30: 1229; and are usually developed with the aid ofcomputerized molecular modeling. Generally, peptidomimetics arestructurally similar to a paradigm polypeptide (i.e., a polypeptide thathas a biochemical property or pharmacological activity), but have one ormore peptide linkages optionally replaced by a linkage selected from thegroup consisting of: —CH₂NH—, —CH₂S—, CH₂—CH₂—, —CH═CH—(cis and trans),—COCH₂—, —CH(OH)CH₂—, and —CH₂SO—, by methods known in the art andfurther described in the following references: Spatola, A. F. in“Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins,” B.Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Spatola, A. F.,Veea Data (arch 1983), Vol. 1, Issue 3, “Peptide Backbone Modifications”(general review); Morley, J. S., Trends. Pharm. Sci., (1980) pp. 463468(general review); Hudson, D. et al., Int. J. Pept. Prot. Res., (1979)14:177-185 (—CH₂ NH—, CH₂CH₂—); Spatola, A. F. et al., Life Sci. (1986)38:1243-1249 (—CH₂—S—); Harm, M. M., J. Chem. Soc. Perkin Trans I (1982)307-314 (—CH═CH—, cis and trans); Almquist, R. G. et al., J. Med. Chem.,(1980) 23:1392-1398 (—COCH₂—); Jennings-White, C. et al., TetrahedronLett., (1982) 23:2533 (—COCH₂—) Szelke, M. et al., European Appln., EP45665 (1982) CA: 97:39405 (1982) (—CH(OH)CH₂—); Holladay, M. W. et al.,Tetrahedron Lett., (1983) 24:4401-4404 (—C(OH)CH₂—); and Hruby, V. J.,Life Sci., (1982) 31:189-199 (—CH₂—S—). Such peptide mimetics may havesignificant advantages over polypeptide embodiments, including, forexample: more economical production, greater chemical stability,enhanced pharmacological properties (half-life, absorption, potency,efficacy, etc.), altered specificity (e.g., a broad-spectrum ofbiological activities), reduced antigenicity, and others.

Additionally, substitution of one or more amino acids within apolypeptide with a D-amino acid of the same type (e.g., D-lysine inplace of L-lysine) may be used to generate more stable polypeptides andpolypeptides resistant to endogenous proteases.

In one embodiment, the polypeptide can be an antibody. Examples of suchantibodies include single-chain antibodies, chimeric antibodies,monoclonal antibodies, polyclonal antibodies, antibody fragments, Fabfragments, IgA, IgG, IgK, IgD, IgE and humanized antibodies. In oneembodiment, the antibody can bind to a cell adhesion molecule, such as acadherin, integrin or selectin. In another embodiment, the antibody canbind to an extracellular matrix molecule, such as collagen, elastin,fibronectin or laminin. In still another embodiment, the antibody canbind to a receptor, such as an adrenergic receptor, B-cell receptor,complement receptor, cholinergic receptor, estrogen receptor, insulinreceptor, low-density lipoprotein receptor, growth factor receptor orT-cell receptor. Antibodies of the invention can also bind to plateletaggregation factors (e.g., fibrinogen), cell proliferation factors(e.g., growth factors and cytokines), and blood clotting factors (e.g.,fibrinogen). In another embodiment, an antibody can be conjugated to anactive agent, such as a toxin. In another embodiment, the antibody canbe Abciximab (ReoProR)). Abciximab is an Fab fragment of a chimericantibody that binds to beta(3) integrins. Abciximab is specific forplatelet glycoprotein IIb/IIIa receptors, e.g., on blood cells. Humanaortic smooth muscle cells express alpha(v)beta(3) integrins on theirsurface. Treating beta(3) expressing smooth muscle cells may prohibitadhesion of other cells and decrease cellular migration orproliferation, thus reducing restinosis following percutaneous coronaryinterventions (CPI) e.g., stenosis, angioplasty, stenting. Abciximabalso inhibits aggregation of blood platelets.

In one embodiment, the peptide can be a glycopeptide. “Glycopeptide”refers to oligopeptide (e.g. heptapeptide) antibiotics, characterized bya multi-ring peptide core optionally substituted with saccharide groups,such as vancomycin. Examples of glycopeptides included in thisdefinition may be found in “Glycopeptides Classification, Occurrence,and Discovery”, by Raymond C. Rao and Louise W. Crandall, (“Drugs andthe Pharmaceutical Sciences” Volume 63, edited by RamakrishnanNagarajan, published by Marcal Dekker, Inc.). Additional examples ofglycopeptides are disclosed in U.S. Pat. Nos. 4,639,433; 4,643,987;4,497,802; 4,698,327; 5,591,714; 5,840,684; and 5,843,889; in EP 0 802199; EP 0 801 075; EP 0 667 353; WO 97/28812; WO 97/38702; WO 98/52589;WO 98/52592; and in J. Amer. Chem. Soc., 1996, 118, 13107-13108; J.Amer. Chem. Soc., 1997, 119, 12041-12047; and J. Amer. Chem. Soc., 1994,116, 4573-4590. Representative glycopeptides include those identified asA477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850A84575, AB-65, Actaplanin, Actinoidin, Ardacin, Avoparcin, Azureomycin,Balhimycin, Chloroorientiein, Chloropolysporin, Decaplanin,-demethylvancomycin, Eremomycin, Galacardin, Helvecardin, Izupeptin,Kibdelin, LL-AM374, Mannopeptin, MM45289, MM47756, MM47761, MM49721,MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653,Orenticin, Parvodicin, Ristocetin, Ristomycin, Synmonicin, Teicoplanin,UK-68597, UK-69542, UK-72051, Vancomycin, and the like. The term“glycopeptide” or “glycopeptide antibiotic” as used herein is alsointended to include the general class of glycopeptides disclosed aboveon which the sugar moiety is absent, i.e. the aglycone series ofglycopeptides. For example, removal of the disaccharide moiety appendedto the phenol on vancomycin by mild hydrolysis gives vancomycinaglycone. Also included within the scope of the term “glycopeptideantibiotics” are synthetic derivatives of the general class ofglycopeptides disclosed above, included alkylated and acylatedderivatives. Additionally, within the scope of this term areglycopeptides that have been further appended with additional saccharideresidues, especially aminoglycosides, in a manner similar tovancosamine.

The term “lipidated glycopeptide” refers specifically to thoseglycopeptide antibiotics which have been synthetically modified tocontain a lipid substituent. As used herein, the term “lipidsubstituent” refers to any substituent contains 5 or more carbon atoms,preferably, 10 to 40 carbon atoms. The lipid substituent may optionallycontain from 1 to 6 heteroatoms selected from halo, oxygen, nitrogen,sulfur and phosphorous. Lipidated glycopeptide antibiotics arewell-known in the art. See, for example, in U.S. Pat. Nos. 5,840,684,5,843,889, 5,916,873, 5,919,756, 5,952,310, 5,977,062, 5,977,063, EP667, 353, WO 98/52589, WO 99/56760, WO 00/04044, WO 00/39156, thedisclosures of which are incorporated herein by reference in theirentirety.

Anti-inflammatory agents include, e.g., analgesics (e.g., NSAIDS andsalicylates), antirheumatic agents, gastrointestinal agents, goutpreparations, hormones (glucocorticoids), nasal preparations, ophthalmicpreparations, otic preparations (e.g., antibiotic and steroidcombinations), respiratory agents, and skin & mucous membrane agents.See, Physician's Desk Reference, 2001 Edition. Specifically, theanti-inflammatory agent can include dexamethasone, which is chemicallydesignated as (11β,16α)-9-fluoro-11,17,21-trihydroxy-1,6-methylpregna-1,4-diene-3,20-dione.Alternatively, the anti-inflammatory agent can include sirolimus(rapamycin), which is a triene macrolide antibiotic isolated fromStreptomyces hygroscopicus.

Anti-platelet or anti-coagulation agents include, e.g., Coumadin®(DuPont), Fragmin® (Pharmacia & Upjohn), Heparin® (Wyeth-Ayerst),Lovenox®, Normiflo®, Orgaran® (Organon), Aggrastat® (Merck), Agrylin®D(Roberts), Ecotrin® (Smithkline Beecham), Flolan® (Glaxo Wellcome),Halfprin® (Kramer), Integrillin® (COR Therapeutics), Integrillin® (Key),Persantine® (Boehringer Ingelheim), Plavix® (Bristol-Myers Squibb),ReoPro® (Centecor), Ticlid® (Roche), Abbokinase® (Abbtt), Activase®(Genentech), Eminase® (Roberts), and Strepase® (Astra). See, Physician'sDesk Reference, 2001 Edition. Specifically, the anti-platelet oranti-coagulation agent can include trapidil (avantrin), cilostazol,heparin, hirudin, or ilprost.

Trapidil is chemically designated asN,N-dimethyl-5-methyl-[1,2,4]triazolo[1,-5-a]pyrimidin-7-amine.

Cilostazol is chemically designated as6-[(1-cyclohexyl-1H-tetrazol-5-yl)-butoxy]-3,4-dihydro-2(1H)-quinolinone.

Heparin is a glycosaminoglycan with anticoagulant activity; aheterogeneous mixture of vatiably sulfonated polysaccharide chainscomposed of repeating units of D-glucosamine and either L-iduronic orD-glucuronic acids.

Hirudin is an anticoagulant protein extracted from leeches, e.g., Hirudoimiedicinalis.

Iloprost is chemically designated as5-[Hexahydro-5-hydroxy-4-(3-hydroxy-4-methyl-1-octen-6-ynyl)-2(1H)pentalenylidene]pentanoicacid.

The immune suppressive agent can include, e.g., Azathioprine® (Roxane),BayRho-D® (Bayer Biological), CellCept® (Roche Laboratories), Imuran®((Glaxo Wellcome), MiCRhoGAM® (Ortho-Clinical Diagnostics), Neoran®(Novartis), Orthoclone OKT3® (Ortho Biotech), Prograf® (Fujisawa),PhoGAM® (Ortho-Clinical Diagnostics), Sandimmune® (Novartis), Simulect®(Novartis), and Zenapax® (Roche Laboratories).

Specifically, the immune suppressive agent can include rapamycin orthalidomide.

Rapamycin is a triene macrolide isolated from Streptomyceshygroscopicus.

Thalidomide is chemically designated as2-(2,6-dioxo-3-piperidinyl)-1H-iso-indole-1,3(2H)-dione.

Anti-cancer or anti-cell proliferation agents include, e.g., nucleotideand nucleoside analogs, such as 2-chloro-deoxyadenosine, adjunctantineoplastic agents, alkylating agents, nitrogen mustards,nitrosoureas, antibiotics, antimetabolites, hormonalagonists/antagonists, androgens, antiandrogens, antiestrogens, estrogen& nitrogen mustard combinations, gonadotropin releasing hotmone (GNRH)analogues, progestrins, immunomodulators, miscellaneous antineoplastics,photosensitizing agents, and skin & mucous membrane agents. See,Physician's Desk Reference, 2001 Edition.

Suitable adjunct antineoplastic agents include Anzemet® (Hoeschst MarionRoussel), Aredia® (Novartis), Didronel® (MGI), Diflucan® Pfizer),Epogen® (Amgen), Ergamisol® (Janssen), Ethyol® (Alza), Kytril®(SmithKline Beecham), Leucovorin® (Immunex), Leucovorin® (GlaxoWellcome), Leucovorin® (Astra), Leukine®) (Immunex), Marinol® (Roxane),Mesnex® (Bristol-Myers Squibb Oncology/Immunology, Neupogen (Amgen),Procrit® (Ortho Biotech), Salagen®D (MGI), Sandostatin®D (Novartis),Zinecard® (Pharmacia & Upjohn), Zofran® (Glaxo Wellcome) and Zyloprim®(Glaxo Wellcome).

Suitable miscellaneous alkylating agents include Myleran® (GlaxoWellcome), Paraplatin®D (Bristol-Myers Squibb Oncology/Immunology),Platinol® (Bristol-Myers Squibb Oncology/Immunology) and Thioplex®(Immunex).

Suitable nitrogen mustards include Alkeran® (Glaxo Wellcome), Cytoxan®(Bristol-Myers Squibb Oncology/Immunology), Ifex® (Bristol-Myers SquibbOncology/Immunology), Leukeran® (Glaxo Wellcome) and Mustargen® (Merck).

Suitable nitrosoureas include BiCNU® (Bristol-Myers SquibbOncology/Immunology), CeeNU® (Bristol-Myers Squibb Oncology/Immunology),Gliadel® (Rhône-Poulenc Rover) and Zanosar® (Pharmacia & Upjohn).

Suitable antibiotics include Adriamycin PFS/RDF® (Pharmacia & Upjohn),Blenoxane® (Bristol-Myers Squibb Oncology/Immunology), Cerubidine®(Bedford), Cosmegen® Merck), DaunoXome® (NeXstar), Doxil® (Sequus),Doxorubicin Hydrochloride® (Astra), Idamycin® PFS (Pharmacia & Upjohn),Mithracin® (Bayer), Mitamnycin® (Bristol-Myers SquibbOncology/Immunology), Nipen®D (SuperGen), Novantrone® (Immunex) andRubex® (Bristol-Myers Squibb Oncology/Immunology).

Suitable antimetabolites include Cytostar-U® (Pharmacia & Upjohn),Fludara®b (Berlex), Sterile FUDR® (Roche Laboratories), Leustatin®(Ortho Biotech), Methotrexate® (Immunex), Parinethol® (Glaxo Wellcome),Thioguanine® (Glaxo Wellcome) and Xeloda® (Roche Laboratories).

Suitable androgens include Nilandron® (Hoechst Marion Roussel) andTeslac® (Bristol-Myers Squibb Oncology/Immunology).

Suitable antiandrogens include Casodex® (Zeneca) and Eulexin®(Schering).

Suitable antiestrogens include Arimidex® (Zeneca), Fareston®g(Schering), Femara® (Novartis) and Nolvadex® (Zeneca).

Suitable estrogen & nitrogen mustard combinations include Emcyt®(Pharmacia & Upjohn).

Suitable estrogens include Estrace® (Bristol-Myers Squibb) and Estrab®(Solvay).

Suitable gonadotropin releasing hormone (GNRH) analogues include LeupronDepot® (TAP) and Zoladex®) (Zeneca).

Suitable progestins include Depo-Provera® (Pharmacia & Upjohn) andMegace® (Bristol-Myers Squibb Oncology/Immunology).

Suitable immunomodulators include Erganisol® (Janssen) and Proleukin®(Chiron Corporation).

Suitable miscellaneous antineoplastics include Camptosar® (Pharmacia &Upjohn), Celestone® (Schering), DTIC-Dome® (Bayer), Elspar® (Merck),Etopophos® (Bristol-Myers Squibb Oncology/Immunology), Etopoxide®(Astra), Gemzar® (Lilly), Hexalen® (U.S. Bioscience), Hycantin®(SmithKline Beecham), Hydrea® (Bristol-Myers SquibbOncology/Immunology), Hydroxyurea® (Roxane), Intron A® (Schering),Lysodren® (Bristol-Myers Squibb Oncology/Immunology), Navelbine® (GlaxoWellcome), Oncaspar® (Rhône-Poulenc Rover), Oncovin® (Lilly), Proleukin®(Chiron Corporation), Rituxan® (IDEC), Rituxan® (Genentech), Roferon-A®(Roche Laboratories), Taxol® (Bristol-Myers Squibb Oncology/Immunology),Taxotere® (Rhône-Poulenc Rover), TheraCys® (Pasteur Mérieux Connaught),Tice BCG® (Organon), Velban® (Lilly), VePesid® (Bristol-Myers SquibbOncology/Immunology), Vesanoid® (Roche Laboratories) and Vumon®(Bristol-Myers Squibb Oncology/Immunology).

Suitable photosensitizing agents include Photofrin® (Sanofi).

Specifically, the anti-cancer or anti-cell proliferation agent caninclude Taxol® (paclitaxol), a niticoxide like compound, or NicOx(NCX-4016).

Taxol® (paclitaxol) is chemically designated as5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-acetate2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.

A niticoxide like compound includes any compound (e.g., polymer) towhich is bound a nitric oxide releasing functional group. Suitableniticoxide like compounds are disclosed, e.g., in U.S. Pat. No.5,650,447 and S-nitrosothiol derivative (adduct) of bovine or humanserum albumin. See, e.g., Inhibition of neointimal proliferation inrabbits after vascular injury by a single treatment with a proteinadduct of nitric oxide; David marks et al J. Clin. Invest. (1995);96:2630-2638.

NCX-4016 is chemically designated as 2-acetoxy-benzoate2-(nitroxymethyl)-phenyl ester, and is an antithrombitic agent.

It is appreciated that those skilled in the art understand that the druguseful in the present invention is the biologically active substancepresent in any of the drugs or agents disclosed above. For example,Taxol® (paclitaxol) is typically available as an injectable, slightlyyellow, viscous solution. The drug, however, is a crystalline powderwith the chemical name5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.Physician's Desk Reference (PDR). Medical Economics Company (Montvale,N.J.), (53rd Ed.), pp. 1059-1067.

As used herein, a “residue of a drug” is a radical of a drug having oneor more open valences. Any synthetically feasible atom or atoms of thedrug can be removed to provide the open valence, provided bioactivity issubstantially retained when the radical is attached to a residue ofcompound of formula (VII) or (XI). Based on the linkage that is desired,one skilled in the art can select suitably functionalized startingmaterials that can be derived from a drug using procedures that areknown in the art.

The residue of a drug can be formed employing any suitable reagents andreaction conditions. Suitable reagents and reaction conditions aredisclosed, e.g., in Advanced Organic Chemistry, Part B: Reactions andSynthesis, Second Edition, Carey and Sundberg (1983); Advanced OrganicChemistry, Reactions Mechanisms, and Structure, Second Edition, March(1977); and Comprehensive Organic Transformations, Second Edition,Larock (1999).

The polymer/drug linkage can degrade to provide a suitable and effectiveamount of drug. Any suitable and effective amount of drug can bereleased and will typically depend, e.g., on the specific polymer, drug,and polymer/drug linkage chosen. Typically, up to about 100% of the drugcan be released from the polymer/drug. Specifically, up to about 90%, upto 75%, up to 50%, or up to 25% of the drug can be released from thepolymer/drug. Factors that typically affect the amount of the drug thatis released from the polymer/drug include, e.g., the nature and amountof polymer, the nature and amount of drug, the nature of thepolymer/drug linkage, and the nature and amount of additional substancespresent in the formulation.

The polymer/drug linkage can degrade over a period of time to providethe suitable and effective amount of drug. Any suitable and effectiveperiod of time can be chosen. Typically, the suitable and effectiveamount of drug can be released in about twenty-four hours, in aboutseven days, in about thirty days, in about ninety days, or in about onehundred and twenty days. Factors that typically affect the length oftime in which the drug is released from the polymer/drug include, e.g.,the nature and amount of polymer, the nature and amount of drug, thenature of the polymer/drug linkage, and the nature and amount ofadditional substances present in the formulation.

Polymer/Linker/Drug Linkage

In addition to being directly linked to the residue of a compound offormula (VII) or (XI), the residue of a drug can also be linked to theresidue of a compound of formula (VII) or (XI) by a suitable linker. Thestructure of the linker is not crucial, provided the resulting compoundof the invention has an effective therapeutic index as a drug.

Suitable linkers include linkers that separate the residue of a compoundof formula (VII) or (XI) and the residue of a drug by about 5 angstromsto about 200 angstroms, inclusive, in length. Other suitable linkersinclude linkers that separate the residue of a compound of formula (VII)or (I) and the residue of a drug by about 5 angstroms to about 100angstroms, inclusive, in length, as well as linkers that separate theresidue of a compound of formula (VII) or (XI) and the residue of a drugby about 5 angstroms to about 50 angstroms, or by about 5 angstroms toabout 25 angstroms, inclusive, in length.

The linker can be linked to any synthetically feasible position on theresidue of a compound of formula (VII) or (XI). Based on the linkagethat is desired, one skilled in the art can select suitablyfunctionalized starting materials that can be derived from a compound offormula (VII) or (XI) and a drug using procedures that are known in theart.

The linker can conveniently be linked to the residue of a compound offormula (VII) or (XI) or to the residue of a drug through an amide(e.g., —N(R)C(═O)— or —C(═O)N(R)—), ester (e.g., —OC(═O)— or —C(═O)O—),ether (e.g., —O—), ketone (e.g., —C(═O)—) thioether (e.g., —S—),sulfinyl (e.g., —S(O)—), sulfonyl (e.g., —S(O)₂—), disulfide (e.g.,—S—S—), amino (e.g., —N(R)—) or a direct (e.g., C—C) linkage, whereineach R is independently H or (C₁-C₆)alkyl. The linkage can be formedfrom suitably functionalized starting materials using syntheticprocedures that are known in the art. Based on the linkage that isdesired, one skilled in the art can select suitably functional startingmaterials that can be derived from a residue of a compound of formula(VII) or (I), a residue of a drug, and from a given linker usingprocedures that are known in the art.

Specifically, the linker can be a divalent radical of the formula W-A-Qwherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl, (C₂-C₂₄)alkynyl,(C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl wherein W and Q are eachindependently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—,—S(O)—, —S(O)₂—, —S—S—, —N(R)—, C(═O)—, or a direct bond (i.e., W and/orQ is absent); wherein each R is independently H or (C₁-C₆)alkyl.

Specifically, the linker can be a divalent radical of the formulaW—(CH₂)-Q wherein, n is between about 1 and about 20, between about 1and about 15, between about 2 and about 10, between about 2 and about 6,or between about 4 and about 6; wherein W and Q are each independently—N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—,—S—S—, —C(═O)—, —N(R)—, or a direct bond (i.e., W and/or Q is absent);wherein each R is independently H or (C₁-C₆)alkyl.

Specifically, W and Q can each independently be —N(R)C(═O)—,—C(═O)N(R)—, —OC(═O)—, —N(R)—, —C(═O)O—, —O—, or a direct bond (i.e., Wand/or Q is absent).

Specifically, the linker can be a divalent radical formed from asaccharide.

Specifically, the linker can be a divalent radical formed from acyclodextrin.

Specifically, the linker can be a divalent radical, i.e., 1,ω-divalentradicals formed from a peptide or an amino acid. The peptide cancomprise 2 to about 25 amino acids, 2 to about 15 amino acids, or 2 toabout 12 amino acids.

Specifically, the peptide can be poly-L-lysine (i.e.,[—NHCH[(CH₂)₄NH₂]CO—]_(m)-Q, wherein Q is H, (C₁-C₁₄)alkyl, or asuitable carboxy protecting group; and wherein m is about 2 to about 25.Specifically, the poly-L-lysine can contain about 5 to about 15 residues(i.e., m is between about 5 and about 15). More specifically, thepoly-L-lysine can contain about 8 to about 11 residues (i.e., m isbetween about 8 and about 11).

Specifically, the peptide can be poly-L-glutamic acid, poly-L-asparticacid, poly-L-histidine, poly-L-ornithine, poly-L-serine,poly-L-threonine, poly-L-tyrosine, poly-L-leucine,poly-L-lysine-L-phenylalanine, poly-L-arginine, orpoly-L-lysine-L-tyrosine.

Specifically, the linker can be prepared from 1,6-diaminohexaneH₂N(CH₂)₆NH₂, 1,5-diaminopentane H₂N(CH₂)NH₂, 1,4-diaminobutane H₂N(CH₂)₄NH₂, or 1,3-diaminopropane H₂N(CH₂)₃NH₂.

One or more drugs can be linked to the polymer through a linker.Specifically, the residue of each of the drugs can each be linked to theresidue of the polymer through a linker. Any suitable number of drugs(i.e., residues thereof) can be linked to the polymer (i.e., residuethereof) through a linker. The number of drugs that can be linked to thepolymer, through a linker, can typically depend upon the molecularweight of the polymer. For example, for a compound of formula (VII),wherein n is about 50 to about 150, up to about 450 drugs (i.e.,residues thereof) can be linked to the polymer (i.e., residue thereof)through a linker, up to about 300 drugs (i.e., residues thereof) can belinked to the polymer (i.e., residue thereof) through a linker, or up toabout 150 drugs (i.e., residues thereof) can be linked to the polymer(i.e., residue thereof) through a linker. Likewise, for a compound offormula (XI), wherein n is about 50 to about 150, up to about 450 drugs(i.e., residues thereof) can be linked to the polymer (i.e., residuethereof) through a linker, up to about 300 drugs (i.e., residuesthereof) can be linked to the polymer (i.e., residue thereof) through alinker, or up to about 150 drugs (i.e., residues thereof) can be linkedto the polymer (i.e., residue thereof) through a linker.

In one embodiment of the present invention, a polymer (i.e., residuethereof) of the present invention can be linked to the linker via thecarboxyl group (e.g., COOR²) of the polymer. Specifically, a compound offormula (VII), wherein R² is independently hydrogen, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; a compound of formula (XI), wherein R² isindependently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; or a combinationthereof, can react with an amino functional group of the linker or ahydroxyl functional group of the linker, to provide a Polymer/Linkerhaving an amide linkage or a Polymer/Linker having a carboxyl esterlinkage, respectively. In another embodiment, the carboxyl group can betransformed into an acyl halide or an acyl anhydride.

In one embodiment of the present invention, a drug (i.e., residuethereof) can be linked to the linker via a carboxyl group (e.g., COOR,wherein R is hydrogen, (C₆-C₁₀)aryl(C₁-C₆)alkyl or (C₁-C₆)alkyl) of thelinker. Specifically, an amino functional group of the drug or ahydroxyl functional group of the drug can react with the carboxyl groupof the linker, to provide a Linker/Drug having an amide linkage or aLinker/Drug having a carboxylic ester linkage, respectively. In anotherembodiment, the carboxyl group of the linker can be transformed into anacyl halide or an acyl anhydride.

The polymer/linker/drug linkage can degrade to provide a suitable andeffective amount of drug. Any suitable and effective amount of drug canbe released and will typically depend, e.g., on the specific polymer,drug, linker, and polymer/linker/drug linkage chosen. Typically, up toabout 100% of the drug can be released from the polymer/linker/drug.Specifically, up to about 90%, up to 75%, up to 50%, or up to 25% of thedrug can be released from the polymer/linker/drug. Factors thattypically affect the amount of the drug that is released from thepolymer/linker/drug include, e.g., the nature and amount of polymer, thenature and amount of drug, the nature and amount of linker, the natureof the polymer/linker/drug linkage, and the nature and amount ofadditional substances present in the formulation.

The polymer/linker/drug linkage can degrade over a period of time toprovide the suitable and effective amount of drug. Any suitable andeffective period of time can be chosen. Typically, the suitable andeffective amount of drug can be released in about twenty-four hours, inabout seven days, in about thirty days, in about ninety days, or inabout one hundred and twenty days. Factors that typically affect thelength of time in which the drug is released from thepolymer/linker/drug include, e.g., the nature and amount of polymer, thenature and amount of drug, the nature of the linker, the nature of thepolymer/linker/drug linkage, and the nature and amount of additionalsubstances present in the formulation.

Polymer Intermixed with Drug

In addition to being linked to one or more drugs, either directly orthrough a linker, a polymer of the present invention can be physicallyintermixed with one or more drugs to provide a formulation.

As used herein, “intermixed” refers to a polymer of the presentinvention physically mixed with a drug or a polymer of the presentinvention physically in contact with a drug.

As used herein, a “formulation” refers to a polymer of the presentinvention intermixed with one or more drugs. The formulation includes apolymer of the present invention having one or more drugs present on thesurface of the polymer, partially embedded in the polymer, or completelyembedded in the polymer. Additionally, the formulation includes apolymer of the present invention and a drug forming a homogeneouscomposition (i.e., a homogeneous formulation).

Any suitable amount of polymer and drug can be employed to provide theformulation. The polymer can be present in about 0.1 wt. % to about 99.9wt. % of the formulation. Typically, the polymer can be present aboveabout 25 wt. % of the formulation; above about 50 wt. % of theformulation; above about 75 wt. % of the formulation; or above about 90wt. % of the formulation. Likewise, the drug can be present in about 0.1wt. % to about 99.9 wt. % of the formulation. Typically, the drug can bepresent above about 5 wt. % of the formulation; above about 10 wt. % ofthe formulation; above about 15 wt. % of the formulation; or above about20 wt. % of the formulation.

The polymer/drug, polymer/linker/drug, formulation, or combinationthereof can be applied, as a polymeric film, onto the surface of amedical device (e.g., stent). The surface of the medical device can becoated with the polymeric film. The polymeric film can have any suitablethickness on the medical device. For example, the thickness of thepolymeric film on the medical device can be about 1 to about 50 micronsthick or about 5 to about 20 microns thick. The polymeric film caneffectively serve as a drug eluting polymeric coating. This drug elutingpolymeric coating can be created by any suitable coating process, e.g.,dip coating, vacuum depositing, or spray coating the polymeric film, onthe medical device. Additionally, the drug eluting polymer coatingsystem can be applied onto the surface of a stent, a vascular deliverycatheter, a delivery balloon, a separate stent cover sheetconfiguration, or a stent drug delivery sleeves type of local drugdelivery systems.

The drug eluting polymer coated stents can be used in conjunction with,e.g., hydrogel-based drug delivery systems.

In addition the above described polymer coated stent, various drugsmixed with hydrogels (see, U.S. Pat. No. 5,610,241) with differentelution rate can be applied on the top of the polymer coated stentsurface as a sandwich type of configuration to deliver anti restenoticagents to the blood vessels and prevent or reduce in-stent restenosis.

Any suitable size of polymer and drug can be employed to provide theformulation. For example, the polymer can have a size of less than about1×10⁻⁴ meters, less than about 1×10⁻⁵ meters, less than about 1×10⁻⁶meters, less than about 1×10⁻⁷ meters, less than about 1×10⁻⁸ meters, orless than about 1×10⁻⁹ meters.

The formulation can degrade to provide a suitable and effective amountof drug. Any suitable and effective amount of drug can be released andwill typically depend, e.g., on the specific formulation chosen.Typically, up to about 100% of the drug can be released from theformulation. Specifically, up to about 90%, up to 75%, up to 50%, or upto 25% of the drug can be released from the formulation. Factors thattypically affect the amount of the drug that is released from theformulation include, e.g., the nature and amount of polymer, the natureand amount of drug, and the nature and amount of additional substancespresent in the formulation.

The formulation can degrade over a period of time to provide thesuitable and effective amount of drug. Any suitable and effective periodof time can be chosen. Typically, the suitable and effective amount ofdrug can be released in about twenty-four hours, in about seven days, inabout thirty days, in about ninety days, or in about one hundred andtwenty days. Factors that typically affect the length of time in whichthe drug is released from the formulation include, e.g., the nature andamount of polymer, the nature and amount of drug, and the nature andamount of additional substances present in the formulation.

The present invention provides for a formulation that includes a polymerof the present invention physically intermixed with one or more drugs.The polymer that is present in the formulation can also be linked,either directly or through a linker, to one or more (e.g., 1, 2, 3, or4) drugs. As such, a polymer of the present invention can be intermixedwith one or more (e.g., 1, 2, 3, or 4) drugs and can be linked, eitherdirectly or through a linker, to one or more (e.g., 1, 2, 3, or 4)drugs.

A polymer of the present invention can include one or more drugs. In oneembodiment, a polymer of the present invention can be physicallyintermixed with one or more drugs. In another embodiment, a polymer ofthe present invention can be linked to one or more drugs, eitherdirectly or through a linker. In another embodiment, a polymer of thepresent invention can be linked to one or more drugs, either directly orthrough a linker, and the resulting polymer can be physically intermixedwith one or more drugs.

A polymer of the present invention, whether or not present in aformulation as described herein, whether or not linked to a drug asdescribed herein, and whether or not intermixed with a drug as describedherein, can be used in medical therapy or medical diagnosis. Forexample, the polymer can be used in the manufacture of a medical device.Suitable medical devices include, e.g., artificial joints, artificialbones, cardiovascular medical devices, stents, shunts, medical devicesuseful in angioplastic therapy, artificial heart valves, artificialby-passes, sutures, artificial arteries, a vascular delivery catheters,a delivery balloons, separate stent cover sheet configurations, andstent drug delivery sleeve types of local drug delivery systems.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

The present invention will now be illustrated by the followingnon-limiting examples.

EXAMPLES

Preparation of copoly(ester amide)s (coPEAs) and copoly(ester urethane)s(coPEURs) (general procedure)

Dry triethylamine (Net) (30.8 mL, 0.22 mole) was added to a mixture ofpredetermined quantities of the di-p-toluenesulfonic acid salt ofbis-(L-α-amino acid)α,ω-alkylene diester (III) and thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (totalamount of (III)+(IV)=0.1 mole), and active diester (V) or activebis-carbonate (IV) (0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into cool water.The separated polymer was thoroughly washed with water, dried at about30° C. under reduced pressure (for final purification of coPEAs andcoPEURs see below). Reduced viscosity data (η_(red)) of the polymerswere obtained in m-cresol at a concentration of 0.5 g/dL and t=25° C.

Preparation of CoPEAs:

Example 1

Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.25)} (1)(compound of formula (VII) wherein m=0.75, p=0.25, n=75, R₁=(CH₂)₄,R₂=Bz, R₃=iso-propyl and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴ (CH₂)₆) (50.168 g, 0.075 mole); the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (total amount of (III)+(IV)=0.1 mole)(14.518 g, 0.025 mole); and di-p-nitrophenyl adipate (V, R¹=(CH₂)₄)(38.833 g, 0.1 mole) in dry N,N-dimethylacetamide (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below), yield is 90%,η_(red)=1.30 dL/g. Mw=32,100, Mn=27,000, Mw/Mn=1.19 (GPC in THF).

Example 2

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.25)} (2)(compound of formula (VII) wherein m=0.75, p=0.25, n=65, R₁=(CH₂)₈,R₂=Bz, R₃=iso-propyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture ofdi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (50.168 g (0.075 mole); the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈)(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below), yield is 91%,η_(red)=1.40 dL/g. Mw=31.300, Mn=21.000, Mw/Mn=1.49 (GPC in THF).Biodegradation (weight loss in %) at 37° C. after 120 h in phosphatebuffer (pH 7.4): ˜0% weight loss in pure buffer, 1-2% in the buffer withα-chymotrypsin (4 mg/10 mL of buffer), 1-2% in the buffer with lipase (4mg/10 mL of buffer).

Example 3

Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)1,6-hexylenediester]}_(0.50)-[N,N′-adipoyl-bis-(L-phenylalanine)-1,6-hexylenediester]_(0.25)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.25)} (3)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=(CH₂)₄, R₂=Bz,R₃=iso-propyl and Bz, and R₄=(CH₂)₆ and Bz).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴ (CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonic acidsalt of bis-(L-phenylalanine)1,6-hexylene diester (III, R⁴=CH₂Ph)(18.924 g, 0.025 mole), the di-p-toluenesulfonic acid salt of L-lysinebenzyl ester (IV) (14.5180 g, 0.025 mole) (total amount of(III)+(IV)=0.1 mole), and di-p-nitrophenyl adipate (V, R¹=(CH₂)₄)(38.833, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL of)(total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification up to negative teston p-nitrophenol and p-toluenesulfonic acid (see below), yield is 94%,η_(red)=1.40 dL/g. Biodegradation (weight loss in %) at 37° C. after 120h in phosphate buffer (pH 7.4): ˜0% in pure buffer, 10% in the bufferwith α-chymotrypsin (4 mg/10 mL of buffer), and 35% in the buffer withlipase (4 mg/10 mL of buffer).

Example 4

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-[N,N′-sebacoyl-(bis-(L-phenylalanine)-1,6-hexylenediester]_(0.25)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.25)} (4)(compound of formula (VII) wherein m¹=0.50, m²=0.25, p=0.25, R₁=(CH₂)₈,R₂=Bz, R₃=iso-propyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of theof di-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylenediester (III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), thedi-p-toluenesulfonic acid salt of bis-(L-phenylalanine)1,6-hexylenediester (III, R⁴=CH₂Ph) (18.924 g, 0.025 mole), the di-p-toluenesulfonicacid salt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (totalamount of (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V,R₁=CH₂)₈) (44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into water. Theseparated polymer was thoroughly washed with water, dried at about 30°C. under reduced pressure. After final purification up to negative teston p-nitrophenol and p-toluenesulfonic acid (see below) yield is 95%,η_(red)=0.77 dL/g. Tg=20.6° C. (DSC).

Example 5

Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.50)} (5)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=((CH₂))₄, R₂=Bz,R₃=iso-propyl, and 4=(CH₂)).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (29.036 g, 0.050 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl adipate (V, R¹=(CH₂)₄)(38.833 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 93%,η_(red)=1.25 dL/g.

Example 6

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.50)} (6)(compound of formula (VII) wherein m=0.50, p=0.50, R₁=(CH₂)₈, R₂=Bz,R₃=iso-propyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(E, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (29.036 g, 0.050 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 95%,η_(red)=1.31 dL/g.

Example 7

Preparation of co-poly-{[N,N′-adipoyl-bis-(L-leucine)1,8-octylenediester]}_(0.90)-{[N,N′-adipoyl-L-lysine benzyl ester]_(0.10)} (7)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₄, R₂=Bz,R₃=iso-propyl, and R₄=(CH₂)₈).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(CH₂)₈) (64.526 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl adipate (V, R¹=(CH₂)₄)(38.833, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 94%,η_(red)=1.21 dL/g.

Example 8

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,4-butylenediester]}_(0.09)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (8)(compound of formula (Vet) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-propyl, and R₄ (CH₂₎ ₄).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylene diester(III, R⁴=(CH₂)₄) (59.477 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈)(44.444 g, 0.1 mole) in dry N,N -dimethylacetamide (DMA) (52.5 mL of)(total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards, the temperatureof the reaction mixture was increased to about 80° C. and stirred forabout 16 hours. The viscous reaction solution was cooled to roomtemperature, diluted with ethanol (150 mL), and poured into water. Theseparated polymer was thoroughly washed with water, dried at 30° C.under reduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 95%,η_(red)=1.28 dL/g.

Example 9

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester])}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (9)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-propyl, and R₄=(C₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (62.002 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(C₂)₈)(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 96%,η_(red)=1.41 dL/g. Biodegradation (weight loss in %) at 37° C. after 120h in phosphate buffer (pH 7.4): ˜0% in pure buffer, 12% in the bufferwith α-chymotrypsin (4 mg/10 mL of buffer), and 38% in the buffer withlipase (4 mg/10 mL of buffer).

Example 10

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,8-octylenediester]}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (10)(compound of formula (VII) wherein m=_(0.90), p=_(0.10), R₁=(CH₂)₈,R₂=Bz, R₃=iso-propyl, and R₄=(C₂)₈.

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(CH₂)₈) (64.526 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl sebacinate (V, R¹=(CH₂)₈)(44.444 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (V)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at about 30° C. underreduced pressure. After final purification up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below) yield is 97%,η_(red)=1.50 dL/g. Tg 27.5° C. (DSC).

Example 11

Preparation of co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,12-dodecylenediester]}_(0.90)-{[N,N′-sebacoyl-L-lysine benzyl ester]_(0.10)} (11)(compound of formula (VII) wherein m=0.90, p=0.10, R₁=(CH₂)₈, R₂=Bz,R₃=iso-propyl, and R₄=(CH₂)₁₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,12-dodecylenediester (III, R⁴=(CH₂)12) (69.576 g, 0.090 mole), thedi-p-toluenesulfonic acid salt of L-lysine benzyl ester (IV) (5.807 g,0.010 mole) (total amount of (III)+(IV) 0.1 mole), and di-p-nitrophenylsebacinate (V, R¹=(CH₂)₈) (44.444 g, 0.1 mole) in dryN,N-dimethylacetamide (DMA) (52.5 mL) (total volume of DMA and NEt₃ is83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by (V)) at roomtemperature. Afterwards, the temperature of the reaction mixture wasincreased to about 80° C. and stirred for about 16 hours. The viscousreaction solution was cooled to room temperature, diluted with ethanol(150 mL), and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification, yield is 96% up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below), η_(red)=0.68 dL/g.

Example 12

Preparation ofco-poly-{[N,N′-dodecyldicarboxyloyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.90)-{[N,N′-dodecyldicarboxyloyl-L-lysine benzylester]_(0.10)} (12) (compound of formula (VII) wherein m=0.90, p=0.10,R₁=(CH₂)₁₂, R₂=Bz, R₃=iso-propyl, and R₄=(CH₂)₆).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (62.002 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.010 mole) (total amountof (III)+(IV)=0.1 mole), and di-p-nitrophenyl dodecyldicarboxylate (V,R¹=(CH₂)₁₂)(50.055 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5mL) (total volume of DMA and NEt₃ in 83.3 mL, concentration 1.2 mol/L by(III)+(IV) or by (V)) at room temperature. Afterwards the temperature ofthe reaction mixture was increased to about 80° C. and stirred for about16 hours. The viscous reaction solution was cooled to room temperature,diluted with ethanol (150 mL), and poured into water. The separatedpolymer was thoroughly washed with water, dried at 30° C. under reducedpressure. After final purification yield is 96% up to negative test onp-nitrophenol and p-toluenesulfonic acid (see below), η_(red)=1.18 dL/g.

Preparation of Co-PEURs:

Example 13

Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)1,4-butylenediester]}_(0.75)-{[N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25)} (13) (compound of formula (XI) wherein m=0.75, p=0.25,R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₄), and R₆=(CH₂)₃.

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylene diester([H, R⁴═(CH₂)₄) (49.565 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (V) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X) (R⁶=(CH₂)₃ (40.624g, 0.1 mole) in dry N,N-dimethylacetamide DMA) (52.5 mL) (total volumeof DMA and NEt₃ in 83.3 mL, concentration 1.2 mol/L by (III)+(IV) or by(X)) at room temperature. Afterwards, the temperature of the reactionmixture was increased to about 80° C. and stirred for about 16 hours.The viscous reaction solution was cooled to room temperature, and pouredinto water. The separated polymer was thoroughly washed with water,dried at 30° C. under reduced pressure. After final purification up tonegative test on p-nitrophenol and p-toluenesulfonic acid (see below)yield is 63%, η_(red)=0.32 dL/g.

Example 14

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)bis-(L-leucine)-1,4-butylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.25)} (14) (compound of formula (XI) wherein m=0.75,p=0.25, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₄), and R₆=(CH₂)₂—O—(CH₂)₂)

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,4-butylene diester(III, R⁴=(CH₂)₄) (49.565 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, and poured into water. The separated polymer wasthoroughly washed with water, dried at about 30° C. under reducedpressure. After final purification up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below) yield is 78%, η_(red)=0.58 dL/g.Biodegradation (weight loss in %) at 37° C. after 240 h in phosphatebuffer (pH 7.4): 4.7% in pure buffer, 2.2% in the buffer withα-chymotrypsin (4 mg/10 mL of buffer), 4.4% in the buffer with lipase (4mg/10 mL of buffer). Films with d=4 cm and m=500±50 mg on Teflonbacking.

Example 15

Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25)} (15) (compound of formula (XI) wherein m=0.75, p=0.25,n=112, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₆, and R₄=(CH₂)₃.

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (51.668 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X) (R⁶=(CH₂)₃)(40.624 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (X)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature, andpoured into water. The separated polymer was thoroughly washed withwater, dried at about 30° C. under reduced pressure. After finalpurification up to negative test on p-nitrophenol and p-toluenesulfonicacid (see below) yield is 60%, η_(red)=0.53 dL/g. Mw=50,000, Mn=29,900,M_(w)/M_(n)=1.68 (GPC). Biodegradation (weight loss in %) at 37° C.after 180 h in phosphate buffer (pH 7.4): 5.0% in pure buffer, 7.3% inthe buffer with α-chymotrypsin (4 mg/10 mL of buffer), and 8.2% in thebuffer with lipase (4 mg/10 mL of buffer). Films with d=4 cm andm=500±50 mg on Teflon backing.

Example 16

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)L-lysinebenzyl ester]_(0.25)} (16) (compound of formula (XI) wherein m=0.75,p=0.25, n=130, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₆), and R₆=(CH₂)₂—O—(CH₂)₂)

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (51.668 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, and poured into water. The separated polymer wasthoroughly washed with water, dried at about 30° C. under reducedpressure. After final purification up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below) yield is 68%, η_(red)=0.72 dL/g.Mw=61,900, n=38,500, Mw/Mn=1.61 (GPC). Biodegradation (weight loss in %)at 37° C. after 180 h in phosphate buffer (pH 7.4): 4.0% in pure buffer,5.6% in the buffer with α-chymotrypsin (4 mg/10 mL of buffer), and 8.9%in the buffer with lipase (4 mg/10 mL of buffer). Films with d=4 cm andm=500±50 mg on Teflon backing.

Example 17

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.50)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.50)} (17) (compound of formula (XI) wherein m=0.50,p=0.50, n=85, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₆), and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture ofdi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (34.446 g, 0.050 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (29.036 g, 0.050 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, and poured into water. The separated polymer wasthoroughly washed with water, dried at about 30° C. under reducedpressure. After final purification up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below) yield is 80%, η_(red)=0.45 dL/g.M_(w)=37,900, M_(n)=22,300, Mw/Mn=1.70 (GPC).

Example 18

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,6-hexylenediester]}_(0.90)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.10)} (18) (compound of formula (XI) wherein m=0.90,p=0.10, n=115, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₆), and R₆=(C₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,6-hexylene diester(III, R⁴=(CH₂)₆) (62.002 g, 0.090 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.807 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.633 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards, thetemperature of the reaction mixture was increased to about 80° C. andstirred for about 16 hours. The viscous reaction solution was cooled toroom temperature, and poured into water. The separated polymer wasthoroughly washed with water, dried at about 30° C. under reducedpressure. After final purification up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below) yield is 70%, η_(red)=0.74 dL/g.M_(w)=56,500, M_(n)=33,700, M_(w)/M_(n)=1.68 (GPC).

Example 19

Preparation ofco-poly-{[N,N′-trimethylenedioxydicarbonyl-bis-(L-leucine)-1,8-octylenediester]}_(0.75)-{N,N′-trimethylenedioxydicarbonyl-L-lysine benzylester]_(0.25)} (19) (compound of formula (XI) wherein m=0.75, p=0.25,R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₈), and R₆=(CH₂)₃.

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(CH₂)₈) (53.772 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X) (R⁶=(CH₂₎ ₃)(40.624 g, 0.1 mole) in dry N,N-dimethylacetamide DMA) (52.5 mL) (totalvolume of DMA and NEt₃ is 83.3 mL, concentration 1.2 mol/L by (III)+(IV)or by (X)) at room temperature. Afterwards, the temperature of thereaction mixture was increased to about 80° C. and stirred for about 16hours. The viscous reaction solution was cooled to room temperature, andpoured into water. The separated polymer was thoroughly washed withwater, dried at about 30° C. under reduced pressure. After finalpurification up to negative test on p-nitrophenol and p-toluenesulfonicacid (see below) yield is 84%, η_(red)=0.46 dL/g. Biodegradation (weightloss in %) at 37° C. after 240 h in phosphate buffer (pH 7.4): 0.9% inpure buffer, 2.0% in the buffer with a-chymotrypsin (4 mg/10 mL ofbuffer), and 3.7% in the buffer with lipase (4 mg/0 mL of buffer). Filmswith d=4 cm and m=500±50 mg on Teflon backing.

Example 20

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,8-octylenediester]}_(0.75)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.25)} (20) (compound of formula (XI) wherein m=0.75,p=0.25, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₈), and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R₄=(CH₂)₈) (53.772 g, 0.075 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (14.518 g, 0.025 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)R⁶=(CH₂)₂—(CH₂)(43.63 g, 0.1 mole) in dry N,N-dimethylacetamide (DMA)(52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration 1.2mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards thetemperature of the reaction mixture was increased to about 80° C. andstirred for 16 hours. The viscous reaction solution was cooled to roomtemperature, and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification, yield is 76% up to negative test on p-nitrophenoland p-toluenesulfonic acid (see below), η_(red)=0.42 dL/g.

Example 21

Preparation ofco-poly-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-bis-(L-leucine)-1,8-octylenediester]}_(0.90)-{[N,N′-(3-oxapentylene-1,5-dioxydicarbonyl)-L-lysinebenzyl ester]_(0.10)} (21) (compound of formula (XI) wherein m=0.90,p=0.10, R₂=Bz, R₃=iso-propyl, R₄=(CH₂)₈), and R₆=(CH₂)₂—O—(CH₂)₂).

Dry triethylamine (30.8 mL, 0.22 mole) was added to the mixture of thedi-p-toluenesulfonic acid salt of bis-(L-leucine)-1,8-octylene diester(III, R⁴=(C₂)₈) (64.5264 g, 0.09 mole), the di-p-toluenesulfonic acidsalt of L-lysine benzyl ester (IV) (5.8072 g, 0.01 mole) (total amountof (III)+(IV)=0.1 mole), and active bis-carbonate (X)(R⁶=(CH₂)₂—O—(CH₂)₂) (43.63 g, 0.1 mole) in dry N,N-dimethylacetamide(DMA) (52.5 mL) (total volume of DMA and NEt₃ is 83.3 mL, concentration1.2 mol/L by (III)+(IV) or by (X)) at room temperature. Afterwards thetemperature of the reaction mixture was increased to about 80° C. andstirred for 16 hours. The viscous reaction solution was cooled to roomtemperature, and poured into water. The separated polymer was thoroughlywashed with water, dried at about 30° C. under reduced pressure. Afterfinal purification up to negative test on p-nitrophenol andp-toluenesulfonic acid (see below) yield is 63%, η_(red)=0.51 dL/g.

Example 22 Deprotection of Polymeric Benzyl Esters (General Procedure)

According to the general procedure described herein for the preparationof coPEAs and coPEURs, the polymers were obtained as the benzyl esterforms. For the preparation of the corresponding polymers having freeCOOH groups, these polymers having the benzyl esters were subjected tocatalytic debenzylation using hydrogen (H₂) gas and palladium (Pd) blackas a catalyst. Suitable reaction conditions are available, e.g., in T.W. Greene, Protecting Groups In Organic Synthesis; Wiley: New York,1981; J. March, Advanced Organic Chemistry. Reactions, Mechanisms andStructure, (2nd Ed.), McGraw Hill: New York, 1977; F. Carey and R.Sundberg, Advanced Organic Chemistry Part B: Reactions and Synthesis,(2nd Ed.), Plenum: New York, 1977; and references cited therein.

(A.) Deprotection of Polymeric Benzyl Esters (coPEAs)

Palladium black catalyst (3.0 g) was added to a solution of the polymer(benzyl ester form) (10 g) in ethanol (100 mL), and dry gaseous hydrogenwas bubbled through the solution for about 10 hours to about 20 hours. Amagnetic stirrer was used to agitate the solution. After catalytichydrogenolysis was complete, the reaction mixture was filtered, andclear and colorless solutions were obtained.

(B.) Deprotection of Polymeric Benzyl Esters (coPEURs)

Palladium black catalyst (3.0 g) was added to a solution of the polymer(benzyl ester form) (10 g) in ethyl acetate (100 mL), and dry gaseoushydrogen was bubbled through the solution for about 10 hours to about 30hours. A magnetic stirrer was used to agitate the solution. Aftercatalytic hydrogenolysis was complete, the reaction mixture wasfiltered, and clear and colorless solutions were obtained

After deprotection of the polymers, no substantial change of molecularweight or polydispersity was observed. For example, for the compound (2)from Table 3 (i.e., benzyl ester form) the molecular weightcharacteristics were as follows: Mw=31.300, Mn=21.000, Mw/Mn=1.49. Afterhydrogenolysis, molecular weight characteristics are: Mw=40.900,Mn=28.000, and Mw/M_(n)=1.46.

Example 23 Purification of the Benzyl Ester Polymers (GeneralProcedures)

After the polymers were precipitated in water and thoroughly washed withwater, the solvent (DMA) and p-toluenesulfonic acid salt oftriethylamine were removed (nearly to completion). However, the polymersstill contain a significant amount of by-product of the polycondensation(e.g., p-nitrophenol) which was removed as described below.

(A.) Purification of coPEAs

The polymer obtained above (10 g) was dissolved in ethanol (50 mL, 95%).The solution was filtered and the polymer was precipitated in ethylacetate (1.0 L), where it separates as tar like mass, and was keptovernight in refrigerator. The ethyl acetate was removed and a freshportion of ethyl acetate (1.0 L) was added to the tar like mass and keptovernight in refrigerator again. This procedure was repeated until anegative test on p-nitrophenol (see below) was obtained. Normally it wasrepeated for 1-2 times. After such a treatment, p-nitrophenol (which ismore soluble in ethylacetate than in water), was nearly completelyremoved from the polymers. The obtained tar like mass was dried,dissolved in 95% ethanol, precipitated in distilled water as arubber-like mass, and dried at about 60° C. under reduced pressure.Yields of purified coPEAs were up to about 97%.

(B.) Purification of coPEURs

The polymer obtained above (10 g) was dissolved in chloroform (100 mL),cast as a thin film onto a cylindrical glass vessel's (d=400-500 mm)inner surface, dried at room temperature, thoroughly washed with water,and dried again. The film obtained was dissolved in dimethylformamide(DMF), and the polymer was precipitated in water. A rubber-like polymerwas collected and dried at about 35° C. to about 40° C. under reducedpressure. This procedure was repeated for several times, until anegative test on p-nitrophenol was obtained (see below). Normally it wasrepeated about 3-4 times. After such a treatment, the yields of coPEURsdecreased to ≦80%, however the viscosities increased, which is believedto be the result of the loss of low-molecular-weight fractions.

(C.) Purification of Deprotected Polymers (Polyacids)

After deprotection, polymers were purified by precipitation from anethanol solution in water. A rubber-like mass was collected and dried atroom temperature under reduced pressure.

Example 25 4-AminoTEMPO Attachment and its Biodegradation and FreeRadicals Release Study

For this study the co-PEA of the following structure was chosen:

(The hydrogenolysis product of the Example 2) which revealed excellentelasticity (elongation at break ca. 1000%) and was used in in vivo“stent experiments”.

4-AminoTEMPO (TAM) was attached to this polyacid usingcarbonyldiimidazol (Im₂CO) as a condensing agent. In typical procedure 1g of polyacid was dissolved in 10 mL of purified, freshly distilledchloroform. A molar equivalent of carbonyldiimidazole was added at roomtemperature and stirred. A molar equivalent of TAM was added, stirredfor 4 h, and kept at r. t. overnight. The solution was filtered and castonto a hydrophobic surface. Chloroform was evaporated to dryness. Theobtained film was thoroughly washed with distilled water and dried underreduced pressure at r.t. An elastic, light red-brown film was obtained.The degree of TAM attachment was 90-95%, determined by UVspectrophotometry in ethanol solution at 250 nm (Polymer does not absorbat this wavelength).

After TAM attachment, the polymer retained elastic properties. Itdegraded by lipase according to nearly zero order biodegradationkinetics (that is ideal for drug controlled release devices) whileretaining the film's integrity whereas the starting polyacid completelydegraded and/or disintegrated within 48 h in slightly alkaline buffersolution in the presence of lipase). TAM attached polymer is designatedas GJ-2(TAM).

For the biodegradation study, the film of GJ-2(TAM) was obtained, it wasdissolved in 10 mL of chloroform, and a Teflon disk of d=4 cm wascovered by this solution for several times and evaporated so that theweight of dried polymeric coating was ca. 500 mg. The disc was placed ina lipase solution (4 mg of the enzyme in 10 mL of phosphate buffer withpH 7.4. 6 mL of the enzyme was dissolved in 15 mL of the buffer—10 mLwas used for biodegradation experiment, 5 mL—for the compensation in UVmeasurements) and placed in thermostat at 37° C. The enzyme solution waschanged every 24 h. Every 24 h the film was removed, dried with filerpaper and weighed. The buffer solution was analyzed by UV-spectroscopyat 250 nm since the polymeric degradation products don't absorb at thiswavelength. The same solution of the enzyme was used for thecompensation.

The obtained results indicate that both biodegradation (weight loss) ofthe polymer and TAM releasing are very close to zero order kinetics.

Since the amide bond through which the TAM is attached to the polymer israther stable under the biodegradation conditions, it is expected thatTAM is released to the polymeric debris. At the same time thecalibration curve of TAM in buffer was used for quantitativemeasurements. Therefore, the amount of TAM (in mg), determined byUV-spectroscopy, corresponds to the free TAM in mg (in mg/equivalent).

After 216 h (9 days) biodegradation polymer lost Ca. 11% of the weight,and ca. 8% of the attached TAM was released This, along withbiodegradation and TAM releasing profiles, indicates that the TAMreleasing is determined by the erosion of the polymeric film.

The results of the biodegradation (weight loss in mg/cm²) of4-AminoTEMPO (TAM), attached to a co-PEA of the present invention, andthe kinetics of nitroxyl radical release from 4-AminoTEMPO (TAM),attached to a co-PEA of the present invention, are shown in the chartsbelow. FIG. 1 illustrates the biodegradation (weight loss in mg/cm²) of4-Amino TEMPO (TAM) attached to a representative compound of the presentinvention. FIG. 2 illustrates the kinetics of nitroxyl radical releasefrom 4-Amino TEMPO (TAM) attached to a representative compound of thepresent invention.

Example 24 Test on Purity (General Procedure)

The coPEA or coPEUR (200-250 mg) was dissolved in a boiling 10% watersolution of NaOH (5.0 mL), and the resulting solution was analyzed usingUV-VIS spectrophotometer (Specord UV-VIS, Carl Zeiss, Jena, cell of 4mL, 1=1,0 cm). The absence of the absorption in the region of 250-280 nm(TosO⁻) and at 430 nm (O₂NC₆H₄O⁻) indicates that neitherp-toluenesulfonic acid nor p-nitrophenol exists in the polymeric sampleto any appreciable degree. It is noted that in alkaline media,p-nitrophenol does not absorb in UV region. As such, its absorption doesnot overlap the absorption of p-toluenesulfonic acid.

The structure of the benzylated polymers prepared in Examples 1-21 isgiven in the Tables below.

Example 25

TABLE I (VII)

Compound R₁ R₂ R₃ R₄ m p n  (1) (CH₂)₄ Bz iso-propyl (CH₂)₆ 0.75 0.25 75 (2) (CH₂)₈ Bz iso-propyl (CH₂)₆ 0.75 0.25 65  (3) (CH₂)₄ Bz iso-propyland Bz (CH₂)₆ 0.75(0.50 + 0.25) 0.25 —  (4) (CH₂)₈ Bz iso-propyl (CH₂)₆0.75(0.50 + 0.25) 0.25 —  (5) (CH₂)₄ Bz iso-propyl (CH₂)₆ 0.50 0.50 — (6) (CH₂)₈ Bz iso-propyl (CH₂)₆ 0.50 0.50 —  (7) (CH₂)₄ Bz iso-propyl(CH₂)₈ 0.90 0.10 —  (8) (CH₂)₈ Bz iso-propyl (CH₂)₄ 0.90 0.10 —  (9)(CH₂)₈ Bz iso-propyl (CH₂)₆ 0.90 0.10 — (10) (CH₂)₈ Bz iso-propyl (CH₂)₈0.90 0.10 — (11) (CH₂)₈ Bz iso-propyl  (CH₂)₁₂ 0.90 0.10 — (12)  (CH₂)₁₂Bz iso-propyl (CH₂)₆ 0.90 0.10 —

Example 26

TABLE II (XI)

Compound R₂ R₃ R₄ R₆ m p n (13) Bz iso-propyl (CH₂)₄ (CH₂)₃ 0.75 0.25 —(14) Bz iso-propyl (CH₂)₄ (CH₂)₂—O—(CH₂)₂ 0.75 0.25 — (15) Bz iso-propyl(CH₂)₆ (CH₂)₃ 0.75 0.25 112 (16) Bz iso-propyl (CH₂)₆ (CH₂)₂—O—(CH₂)₂0.75 0.25 130 (17) Bz iso-propyl (CH₂)₆ (CH₂)₂—O—(CH₂)₂ 0.50 0.50  85(18) Bz iso-propyl (CH₂)₆ (CH₂)₂—O—(CH₂)₂ 0.90 0.10 115 (19) Bziso-propyl (CH₂)₈ (CH₂)₃ 0.75 0.25 — (20) Bz iso-propyl (CH₂)₈(CH₂)₂—O—(CH₂)₂ 0.75 0.25 — (21) Bz iso-propyl (CH₂)₈ (CH₂)₂—O—(CH₂)₂0.90 0.10 —

The physical properties of the polymers prepared in Examples 1-12 aregiven in Table III.

Example 27

TABLE III Mw/Mn (GPC B.W.L. Tg Compound Yield (%) η_(red) (dL/g) Mw Mnin THF) B.W.L. (%)¹ B.W.L. (%)² (%)³ (DSC) (1) 90 1.30 32,100 27,0001.19 (2) 91 1.40 31,300 21,000 1.49 ~0 1-2 1-2 (3) 94 1.40 ~0 10 35 (4)95 0.77 20.6° C. (5) 93 1.25 (6) 95 1.31 (7) 94 1.21 (8) 95 1.28 (9) 961.41 ~0 12 38 (10) 97 1.50 27.5° C. (11) 96 0.68 (12) 96 1.18 (13) 630.32 (14) 78 0.58 4.7⁴ 2.2⁵ 4.4⁶ (15) 60 0.53 50,000 29,900 1.68 5.0⁷7.3⁸ 8.2⁹ (16) 68 0.72 61,900 38,500 1.61 0.4⁷ 5.6⁸ 8.9⁹ (17) 80 0.4537,900 22,300 1.70 (18) 70 0.74 56,500 33,700 1.68 (19) 84 0.46 0.9⁴2.0⁵ 3.7⁶ (20) 76 0.42 (21) 63 0.51 ¹B.W.L. (%) is biodegradation(weight loss %) at 37° C. after 120 h in phosphate buffer (pH 7.4).²B.W.L. (%) is biodegradation (weight loss %) at 37° C. after 120 h inphosphate buffer (pH 7.4) with α-chymotrypsin (4 mg/10 mL of buffer.³B.W.L. (%) is biodegradation (weight loss %) at 37° C. after 120 h inphosphate buffer (pH 7.4) with lipase (4 mg/10 mL of buffer). ⁴B.W.L.(%) is biodegradation (weight loss %) at 37° C. after 240 h in phosphatebuffer (pH 7.4). ⁵B.W.L. (%) is biodegradation (weight loss %) at 37° C.after 240 h in phosphate buffer (pH 7.4) with α-chymotrypsin (4 mg/10 mLof buffer. ⁶B.W.L. (%) is biodegradation (weight loss %) at 37° C. after240 h in phosphate buffer (pH 7.4) with lipase (4 mg/10 mL of buffer).⁷B.W.L. (%) is biodegradation (weight loss %) at 37° C. after 180 h inphosphate buffer (pH 7.4). ⁸B.W.L. (%) is biodegradation (weight loss %)at 37° C. after 180 h in phosphate buffer (pH 7.4) with α-chymotrypsin(4 mg/10 mL of buffer. ⁹B.W.L. (%) is biodegradation (weight loss %) at37° C. after 180 h in phosphate buffer (pH 7.4) with lipase (4 mg/10 mLof buffer).

The benzylated polymers obtained had high Mw in the range 30,000-60,000and narrow polydispersity—Mw/Mn=1.2-1.7 (Determined by GPC for thepolymers, soluble in THF), and possess excellent film-formingproperties. They revealed rather low glass transition temperature(Tg=9-20° C.). The polymers are soluble in common organic solvents likechloroform (all of them), ethanol, (copoly(ester amide)s), ethylacetate(copoly(ester urethane)s), some of them in THF. Both co-PEAs andco-PEURs reveal rather high tendency to in vitro biodegradation. Co-PEAsare more inclined to specific (enzyme catalyzed) hydrolysis, whereasco-PEURs showed the tendency to both specific and non-specific(chemical) hydrolysis.

Example 28 In Vitro Biodegradation Study

In vitro biodegradation studies were performed by weight loss. Standardfilms with d=4 cm and m=450-550 mg (pure films in case ofnon-contractive poly(ester amide)s and films on Teflon backing in caseof contractive poly(ester urethane)s), were placed into the glassvessels containing 10 mL of 0.2 M phosphate buffer solution with pH=7.4(either pure buffer or buffer containing 4 mg of anenzyme-α-chymotrypsin or lipase) and placed at 37° C. The films wereremoved from the solutions after a predetermined time, dried with filterpaper and weighted. Buffer or enzyme solution was changed every 24 h.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A polymer of formula (VII)

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R¹ is independently (C₂-C₂₀)alkyl; each R²is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ isindependently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; and each R⁴ is independently (C₂-C₂₀)alkyl;that is linked to one or more drugs.
 2. The polymer of claim 1 wherein aresidue of the polymer is linked directly to a residue of the drug. 3.The polymer of claim 2 wherein the residue of the polymer is linkeddirectly to the residue of the drug through an amide, ester, ether,amino, ketone, thioether, sulfinyl, sulfonyl, disulfide, or a directlinkage.
 4. The polymer of claim 2 wherein the residue of the polymer islinked directly to the residue of the drug through one of the followinglinkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —C(═O)—,—S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R isindependently H or (C₁-C₆)alkyl.
 5. The polymer of claim 1 wherein aresidue of the polymer is linked to a residue of the drug, through alinker.
 6. The polymer of claim 5 wherein the linker separates theresidue of the polymer and the residue of the drug by about 5 angstromsto about 200 angstroms, inclusive, in length.
 7. The polymer of claim 5wherein (1) the residue of the polymer is linked to the linker and (2)the linker is linked to the residue of the drug, independently, throughan amide, ester, ether, amino, ketone, thioether, sulfinyl, sulfonyl,disulfide, or a direct linkage.
 8. The polymer of claim 5 wherein (1)the residue of the polymer is linked to the linker and (2) the linker islinked to the residue of the drug, independently, through one of thefollowing linkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—C(═O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R isindependently H or (C₁-C₆)alkyl.
 9. The polymer of claim 5 wherein thelinker is a divalent radical of the formula W-A-Q wherein A is(C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl, (C₂-C₂₄)alkynyl, (C₃-C₈)cycloalkyl, or(C₆-C₁₀) aryl, wherein W and Q are each independently —N(R)C(═O)—,—C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O)₂—, —S—S—,—N(R)—, —C(═O)—, or a direct bond; wherein each R is independently H or(C₁-C₆)alkyl.
 10. The polymer of claim 5 wherein the linker is anαω-divalent radical formed from a peptide or an amino acid.
 11. Thepolymer of claim 10 wherein the peptide comprises 2 to about 25 aminoacids.
 12. The polymer of claim 10 wherein the peptide is poly-L-lysine,poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine,poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine,poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-arginine, orpoly-L-lysine-L-tyrosine.
 13. The polymer of claim 1 wherein the one ormore drugs are each independently: a polynucleotide, polypeptide,oligonucleotide, gene therapy agent, nucleotide analog, nucleosideanalog, polynucleic acid decoy, therapeutic antibody, abciximab,anti-inflammatory agent, blood modifier, anti-platelet agent,anti-coagulation agent, immune suppressive agent, anti-neoplastic agent,anti-cancer agent, anti-cell proliferation agent, or nitric oxidereleasing agent.
 14. A formulation comprising a polymer of formula (VII)

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R¹ is independently (C₂-C₂₀)alkyl; each R²is independently hydrogen, or (C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ isindependently hydrogen, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; and each R₄ is independently (C₂C₂₀)alkyl; andone or more drugs.
 15. The formulation of claim 14 wherein the one ormore drugs are each independently: a polynucleotide, polypeptide,oligonucleotide, gene therapy agent, nucleotide analog, nucleosideanalog, polynucleic acid decoy, therapeutic antibody, abciximab,anti-inflammatory agent, blood modifier, anti-platelet agent,anti-coagulation agent, immune suppressive agent, anti-neoplastic agent,anti-cancer agent, anti-cell proliferation agent, or nitric oxidereleasing agent.
 16. A polymer of formula (XI)

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R² is independently hydrogen, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R³ is independently hydrogen,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R⁴ is independently (C₂-C₂₀)alkyl; andeach R⁶ is independently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl;that is linked to one or more drugs.
 17. The polymer of claim 16 whereina residue of the polymer is linked directly to a residue of the drug.18. The polymer of claim 17 wherein the residue of the polymer is linkeddirectly to the residue of the drug through an amide, ester, ether,amino, ketone, thioether, sulfinyl, sulfonyl, disulfide, or a directlinkage.
 19. The polymer of claim 16 wherein the residue of the polymeris linked directly to the residue of the drug through one of thefollowing linkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—,—C(═O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C; wherein each R isindependently H or (C₁-C₆)alkyl.
 20. The polymer of claim 16 wherein aresidue of the polymer is linked to a residue of the drug, through alinker.
 21. The polymer of claim 20 wherein the linker separates theresidue of the polymer and the residue of the drug by about 5 angstromsto about 200 angstroms, inclusive, in length.
 22. The polymer of claim20 wherein (1) the residue of the polymer is linked to the linker and(2) the linker is linked to the residue of the drug, independently,through an amide, ester, ether, amino, ketone, thioether, sulfinyl,sulfonyl, disulfide, or a direct linkage.
 23. The polymer of claim 20wherein (1) the residue of the polymer is linked to the linker and (2)the linker is linked to the residue of the drug, independently, throughone of the following linkages: —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—,—C(═O)O—, —O—, —C(═O)—, —S—, —S(O)—, —S(O)₂—, —S—S—, —N(R)—, or C—C;wherein each R is independently H or (C₁-C₆)alkyl.
 24. The polymer ofclaim 20 wherein the linker is a divalent radical of the formula W-A-Qwherein A is (C₁-C₂₄)alkyl, (C₂-C₂₄)alkenyl, (C₂-C₂₄)alkynyl,(C₃-C₈)cycloalkyl, or (C₆-C₁₀)aryl, wherein W and Q are eachindependently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—,—S(O)—, —S(O)₂—, —S—S—, —N(R)—, —C(═O)—, or a direct bond; wherein eachR is independently H or (C₁-C₆)alkyl.
 25. The polymer of claim 20wherein the linker is a 1, 107 -divalent radical formed from a peptideor an amino acid.
 26. The polymer of claim 25 wherein the peptidecomprises 2 to about 25 amino acids.
 27. The polymer of claim 25 whereinthe peptide is poly-L-lysine, poly-L-glutamic acid, poly-L-asparticacid, poly-L-histidine, poly-L-ornithine, poly-L-serine,poly-L-threonine, poly-L-tyrosine, poly-L-leucine,poly-L-lysine-L-phenylalanine, poly-L-arginine, orpoly-L-lysine-L-tyrosine.
 28. The polymer of claim 16 wherein the one ormore drugs are each independently: a polynucleotide, polypeptide,oligonucleotide, gene therapy agent, nucleotide analog, nucleosideanalog, polynucleic acid decoy, therapeutic antibody, abciximab,anti-inflammatory agent, blood modifier, anti-platelet agent,anti-coagulation agent, immune suppressive agent, anti-neoplastic agent,anti-cancer agent, anti-cell proliferation agent, or nitric oxidereleasing agent.
 29. A formulation comprising a polymer of formula (XI)

wherein m is about 0.1 to about 0.9; p is about 0.9 to about 0.1; n isabout 50 to about 150; each R² is independently hydrogen, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R₃ is independently hydrogen,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or(C₆-C₁₀)aryl(C₁-C₆)alkyl; each R⁴ is independently (C₂-C₂₀)alkyl; andeach R⁶ is independently (C₂-C₂₀)alkyl or (C₂-C₈)alkyloxy(C₂-C₂₀)alkyl;and one or more drugs.
 30. The formulation of claim 29 wherein the oneor more drugs are each independently: a polynucleotide, polypeptide,oligonucleotide, gene therapy agent, nucleotide analog, nucleosideanalog, polynucleic acid decoy, therapeutic antibody, abciximab,anti-inflammatory agent, blood modifier, anti-platelet agent,anti-coagulation agent, immune suppressive agent, anti-neoplastic agent,anti-cancer agent, anti-cell proliferation agent, or nitric oxidereleasing agent.
 31. The polymer of claim 1 wherein each R¹ isindependently (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 32. The polymer of claim 1wherein each R² is independently hydrogen or benzyl.
 33. The polymer ofclaim 1 wherein each R³ is independently iso-butyl or benzyl.
 34. Thepolymer of claim 1 wherein each R⁴ is independently (CH₂)₄, (CH₂)₆,(CH₂)₈, or (CH₂)₁₂.
 35. The polymer of claim 1 wherein p/(p+m) is about0.9 to about 0.1.
 36. The polymer of claim 1 wherein m/(p+m) is about0.1 to about 0.9.
 37. The polymer of claim 16 wherein each R² isindependently hydrogen or benzyl.
 38. The polymer of claim 16 whereineach R³ is independently iso-butyl or benzyl.
 39. The polymer of claim16 wherein each R⁴ is independently (CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.40. The polymer of claim 16 wherein each R⁶ is independently (CH₂)₃ or(CH₂)₂—O—(CH₂)₂.
 41. The polymer of claim 16 wherein p/(p+m) is about0.9 to about 0.1.
 42. The polymer of claim 16 wherein m/(p+m) is about0.1 to about 0.9.
 43. The formulation of claim 14 wherein each R¹ isindependently (CH₂)₄, (CH₂)₈, or (CH₂)₁₂.
 44. The formulation of claim14 wherein each R² is independently hydrogen or benzyl.
 45. Theformulation of claim 14 wherein each R³ is independently iso-butyl orbenzyl.
 46. The formulation of claim 14 wherein each R⁴ is independently(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂)₁₂.
 47. The formulation of claim 14wherein p/(p+m) is about 0.9 to about 0.1.
 48. The formulation of claim14 wherein m/(p+m) is about 0.1 to about 0.9.
 49. The formulation ofclaim 29 wherein each R² is independently hydrogen or benzyl.
 50. Theformulation of claim 29 wherein each R³ is independently iso-butyl orbenzyl.
 51. The formulation of claim 29 wherein each R⁴ is independently(CH₂)₄, (CH₂)₆, (CH₂)₈, or (CH₂₎ ₁₂.
 52. The formulation of claim 29wherein each R⁶ is independently (CH₂)₃ or (CH₂)₂—O—(CH₂)₂.
 53. Theformulation of claim 29 wherein p/(p+m) is about 0.9 to about 0.1. 54.The formulation of claim 29 wherein m/(p+m) is about 0.1 to about 0.9.